2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists

ABSTRACT

Compounds of formula I ##STR1## wherein X is ##STR2## or ═N--O--, in which R 4  is hydrogen or halogen, R 1 , R 2 , and R 3  independently represent hydrogen or a C 1-4  alkyl group, and n has a value of zero to four are disclosed. Also disclosed are pharmaceutically acceptable salts of these compounds, pharmaceutical compositions of these compounds or salts with a pharmaceutically acceptable carrier, the use of these materials as N-methyl-D-aspartate receptor antagonists, processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering an effective amount of these compounds, salts or compositions.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention concerns a series of 4-(phosphonoalkylidene)- or 4-(phosphonoalkoxyimino)-2-piperidinecarboxylic acid derivatives useful in the treatment of cerebrovascular disorders.

2. Background Information

Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this excitotoxic action is mediated by the excitatory amino acids, glutamate and aspartate, acting at the N-methyl-D-aspartate (NMDA) receptor. This excitotoxic action is responsible for neuronal loss in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma.

The compounds of the invention, which are active as competitive antagonists of NMDA receptor-mediated ion-channel activation, are thus useful in the treatment of the above disorders. In addition, by this NMDA receptor antagonist action, the compounds of the invention are also useful for treating neurodegenerative disorders, spinal cord injury, and poisoning by exogenous NMDA poisons (for example, some forms of lathyrism). There are no specific therapies for these neurodegenerative disorders, but competitive and noncompetitive NMDA antagonists acting specifically to antagonize excitatory neurotransmission at NMDA receptors offer a novel therapeutic approach to these disorders; B. Meldrum in Neurotoxins and Their Pharmacological Implications. ed. P. Jenner, Raven Press, New York, 1987.

Recent reports in the literature have confirmed the protective action of certain NMDA antagonists in pharmacological models of neurodegenerative disorders (J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J. Pharmacol., (1987) 140:359; R. Gill, A. C. Foster and G. N. Woodruff, J. Neurosci., (1987) 7:3343; S. M. Rothman, J. Thurston, R. E. Hauhart, G. D. Clark and J. S. Solomon, Neurosci., (1987) 21:673; M. P. Goldberg, P. C. Pham and D. W. Choi, Neurosci. Lett., (1987) 80:11).

In addition, U.S. Pat. Nos. 4,746,653; 4,906,621; and 4,898,854 are concerned with phosphonic acid derivatives of 2-piperidine or 2-tetrahydropyridine carboxylates, which are said to be useful as N-methyl-D-aspartate (NMDA) receptor antagonists.

STATEMENT OF THE INVENTION

The invention relates to compounds of the following General Formula I: ##STR3## wherein X is ##STR4## or ═N--O--, in which R₄ is hydrogen or halogen, R₁, R₂, and R₃ independently represent hydrogen or a C₁₋₄ alkyl group, and n is an integer having a value of zero to four and to pharmaceutically acceptable salts of the compounds of Formula I, and pharmaceutical compositions made up of these compounds and salts with pharmaceutically acceptable carriers. These compositions are useful as N-methyl-D-aspartate receptor antagonists. In other aspects, this invention provides processes for preparing these compounds and salts, and methods to treat cerebral diseases by administering to a patient an effective amount of these pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION BRIEF DESCRIPTION OF THE DRAWINGS

This invention will be described with reference to the accompanying drawings in which:

FIG. 1 is a reaction scheme for preparing compounds and salts of the invention as set out in Example 1;

FIG. 2 is a reaction scheme for preparing compounds and salts of the invention as set out in Example 2; and

FIG. 3 is a reaction scheme for preparing compounds and salts of the invention as set out in Example 3.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides compounds and pharmaceutical compositions based on them which are useful as N-methyl-D-aspartate receptor antagonists and in the treatment of cerebral diseases such as cerebral ischemia, cerebral hypoglycemia, epilepsy, anxiety and convulsion.

The Compounds

The compounds of this invention are materials of General Formula I, and pharmaceutically acceptable salts thereof: ##STR5## In this formula X is ##STR6## or ═N--O-- wherein R₄ is hydrogen or a halo, such as fluoro, chloro, bromo or the like. When R₄ is present, it is preferably hydrogen or fluoro. "n" is an integer. It can be 0, 1, 2, 3, or 4. R₁ is hydrogen or a C₁₋₄ alkyl. The term "C₁₋₄ alkyl" means a saturated aliphatic group Of 1, 2, 3 or 4 carbons, either branched or straight chain. "C₁₋₄ alkyls" include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl groups.

R₂ and R₃ are also hydrogen or C₁₋₄ alkyls R₁, R₂ and R₃ are selected independently, but usually, for ease of synthesis, R₂ and R₃ are the same. Methyl and hydrogen are preferred as R₂ and R₃ groups.

Pharmaceutically Acceptable Salts

These compounds can exist as salts. The salt can be formed of the carboxylic acid (i.e., a salt anion replacing a hydrogen R₁), and salts can be formed of the phosphonic acid (i.e., replacing the R₂ and/or the R₃ groups if they are hydrogens with a salt anion). All three positions can be salts.

Pharmaceutically acceptable salts are salts of these compounds which have anions that are pharmaceutically acceptable--i.e., nontoxic. These are preferably metal or ammonium salts of the compounds of the invention having a free phosphono or/and carboxyl group, more particularly alkali metal or alkaline earth metal salts such as the sodium, potassium, magnesium or calcium salt; or advantageously crystallizing ammonium salts derived from ammonia or organic amines, such as monoethylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminoethane or benzyltrimethylammonium hydroxide. In addition, the NH group present in the compounds of the invention can form acid-addition salts of pharmaceutically acceptable inorganic or organic acids, such as of strong mineral acids, for example, hydrohalic, hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acid, for example, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, palmoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acid.

Isomers, etc.

The compounds of the invention contain at least one asymmetric carbon atom. The invention includes individual enantiomers, diastereomers, or mixtures thereof, which may be prepared or isolated by methods known in the art. The compounds of the invention also include geometrical isomers based on the olefin or imine portion. The invention includes individual E-isomers, Z-isomers and mixtures thereof, which may be prepared or isolated by the methods known in the art.

Pharmaceutical Formulations

The compounds of the invention may be administered according to any convenient or effective methods for introducing foreign substances into the blood stream of mammals, such as by oral, rectal, nasal, buccal, vaginal, or parenteral routes. The effective dosage level is, for example, 0.01 to 100 mg/kg, preferably about 0.05 to 50 mg/kg, and may be administered on a regimen of 1-4 times per day. The pharmaceutical formulations comprising the compounds of the invention may be in dosage forms such as tablets, pills, capsules, powders, or granules for oral administration.

Compounds and salts here provided can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic carriers. As mentioned above, such compositions may be prepared for use for parenteral (subcutaneous, intramuscular or intravenous) administration particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration particularly in semisolid forms such as creams and suppositories; for oral or buccal administration particularly in the form of tablets or capsules; or intranasally particularly in the form of powders, nasal drops or aerosols.

The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example as described in Remingtons's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 1975, incorporated by reference. Formulations for parenteral administration may contain as common excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Formulations for vaginal or rectal administration, e.g., suppositories, may contain as excipients, for example, polyalkylene glycols, petroleum jelly, cocoa butter, and the like. Formulations for inhalation administration may be solid and contain as excipients, for example, lactose, or may be aqueous or oily solutions for administration in the form of nasal drops. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.

For oral administration, a pharmaceutically acceptable nontoxic composition can be formed by the incorporation of any of the normally employed excipients, oral dose extenders or carriers such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. Such compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Such compositions may contain 0.1-95% active ingredient, preferably 1-70%, with the remainder being carrier.

The materials of this invention can be employed as the sole active agent in a pharmaceutical composition or can be used in combination with other active ingredients.

The effects of the compounds of the invention can be evaluated in in vitro tests or in vivo animal tests using mammals such as mice, rats, rabbits, dogs and monkeys, or tissues, membranes, receptors or enzyme preparations thereof.

Competition binding for NMDA receptor with radio-labeled known NMDA antagonist is one convenient way to ascertain the ability of the compounds of the invention to bind to target cerebral cells. This evaluation can be made according to the method of J. Lehman et al., 1988. In addition, the ability to antagonize NMDA receptors can be evaluated according to the method of Ferkany et al., 1988.

Preparation of the Compounds

The compounds of the invention can be prepared by three processes set forth in the Schemes 1-3, which are set forth in FIGS. 1-3 respectively.

The processes of Schemes 1, 2 and 3 are fully exemplified in Examples 1, 2 and 3. The schemes illustrate the preparation of both isomers of the "olefin" X group with free acid form at both the phosphonate and the carbonyl functionalities. In this process of Scheme 1, a suitably protected amine, protected carboxylic group ketone 6 is treated with tetramethyl methylene diphosphonate at moderate temperatures. This introduces the desired phosphonate group, as a dialkyl ester. Blocking groups can be removed and various R₁, R₂ and R₃ groups can be varied among H, and the various lower alkyls by hydrolysis and esterification reactions. Schemes 2 and 3 show variations on this general preparative process.

In Schemes 1, 2 and 3, n is generally shown as O. If one wants to have higher values i.e., 1, 2, 3, or 4) for n, and thus longer --(CH₂)_(n) -- chain lengths, these can be attained. A suitably protected carbonyl such as 16 in Scheme 3 can be reacted with a triphenylphosphorane Ph₃ P═CH--(CH₂)_(n) --Z, or a phosphorane ylide generated from (EtO)₂ P(O)--CH₂ (CH₂)_(n) --Z wherein Z is a leaving group such as halo or a methoxy. These materials react in an inert solvent such as THF within a few hours at a moderate temperature to add the ═CH--(CH₂)_(n) --Z group in place of the ketone oxygen. This yields a mixture of isomers which is beneficially separated at this point. The desired isomer is then treated with diethyl phosphate anion --PO₃ Et₂ in an aprotic solvent such as DMF at moderate temperatures (50°-100° C.) for 2-12 hours. This allows the phosphate to displace the Z leaving group and give rise to the full range of n=1, 2, 3 or 4 groups depending upon the particular ═CH(CH₂)_(n) --Z group employed. R₁, R₂ and R₃ can all be varied as previously described.

As shown in Schemes 1, 2 and 3, it is generally desirable to protect the various carbonyl and amine groups for these reactions. These protection-deprotection routes are known in the art.

═X can also be an ##STR7## group, wherein R₄ is a halo instead of H. The R₄ halo can be present as a substituent in the phosphorane reagent, in the phosphonate reagent or the methylene of the tetramethylene diphosphonate reagent. This will insert the R₄ halo at the desired position.

In a final variation, ═X can be ═N--O--. This functionality can be introduced using well-known chemistry.

The reagents H₂ N--O--CH₂ --PO₃ H₂ and H₂ N--O--(CH₂)₂ --PO₃ H₂ are known and available as their HCl acid addition salts. Other equivalent materials, where n=2, 3 or 4, are preparable analogously. These reagents will react with a protected ketone such as 16 from Scheme 3 at a temperature of 0°-100° C., preferably from room temperature to 70° C. in, for example, an appropriate solvent such as water, alcohol, dioxane or THF. This will add the ═N--O--(CH₂)_(n) --PO₃ H₃ group in place of the ketone. Thereafter, the various protecting groups can be removed and the various hydrogens and alkyl groups substituted as R₁, R₂ and R₃ as noted above.

The pharmaceutically acceptable nontoxic salt derivatives of the compounds of Formula I are prepared by treating the free acids with an appropriate amount of pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. The reaction is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0° C. to about 100° C., preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of compounds of Formula I to base used are chosen to provide the ratio desired for any particular salt. For preparing, for example, the calcium salts or magnesium salts, the free acid starting material of Formula I can be treated with at least one-half molar equivalent of pharmaceutically acceptable base to yield a neutral salt. When the aluminum salts of the compounds of Formula I are prepared, at least one third molar equivalent of the pharmaceutically acceptable base are employed if a neutral salt product is desired.

The salt derivatives of the compounds of Formula I can be reconverted to their respective free acids by acidifying said salts with an acid, preferably an inorganic acid, e.g. hydrochloric acid, sulfuric acid, and the like, at temperature of from about 0° C. to about 50° C., preferably at room temperature.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, and under atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative examples. The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.

The following examples and illustrations are intended to illustrate the invention and are not to be construed as being limitations thereon. Reaction Schemes 1, 2 and 3 of FIGS. 1, 2 and 3 correspond to Examples 1, 2 and 3.

EXAMPLE 1 Synthesis of 4-(phosphonomethylidene)-2-piperidinecarboxylic acid (E-isomer and Z-isomer) (Scheme 1)

Commercially available 4-methoxypyridine N-oxide (50 g, 0.4 mol) was dissolved in dichloromethane (200 mL), and to it was added trimethylsilylcyanide (67.4 mL, 0.506 mol) at room temperature. Dimethylcarbamyl chloride (46.5 mL, 0.506 mol) was added dropwise with stirring to the reaction mixture over a 30-min period. The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous potassium Carbonate (100 mL) was added dropwise, and stirring was continued for 15 minutes. The organic layer was separated, dried, and concentrated to afford 2-cyano-4-methoxypyridine 1 (51.5 g, 96%) as an off-white solid.

A solution of 2-cyano-4-methoxypyridine 1 (45 g, 0.34 mol) and 48% aqueous HBr (500 mL) was heated for 72 hours at reflux, then cooled to room temperature and concentrated in vacuo. To the residue was added anhydrous ethanol (1 L); then HCl gas was bubbled through the solution for 10 minutes. After heating overnight at reflux, the mixture was cooled to room temperature and concentrated to afford the desired ethyl ester 2 as a white solid (45.5 g, 80% yield).

This solid (10.1 g, 0.05 mol) was hydrogenated in ethanol/water (1:1, 100 mL) with PtO₂ (5 g) at 60 psi H₂ pressure at 60° C. for 18 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford a crude solid 3 (9.68 g, 90%) as a white solid.

The ethyl ester 3 was dissolved in dichloromethane (150 mL)/anhydrous ethanol (75 mL) and to it was added diisopropylethylamine (15.65 mL) and a solution of di-tert-butyldicarbonate (19.64 g, 0.09 mol) in 180 mL of dichloromethane in four portions. The resultant mixture was stirred at room temperature for 18 h. The reaction mixture was filtered through celite and the filtrate evaporated to dryness at reduced pressure. The residue was dissolved in CHCl₃ and washed with 4% HCl. The organic phase was dried over MgSO₄ and evaporated to dryness at reduced pressure to afford 16.0 g of crude t-Boc-protected product. Purification by chromatography using 600 g flash chromatography silica gel and 30-50% EtOAc/hexane gave 10.01 g of pure t-Boc-N-protected piperidine derivative 4 (39% yield).

The N-protected ester 4 (6.1 g) was heated in 25 mL of t-butylamine at 140° C. for 18 h in a sealed tube to afford, after evaporation of the excess t-butylamine, the desired amide 5 ¹ H NMR (CDCl₃, 300 MHz): δ4.91 (m, 1H, 2-H), 4.20 (m, 2H, 6-H₂), 3.32 (m, 1H, 4-H), 1.72 [s, 9H, C(CH₃)₃ ], 1.51 [s, 9H, C(CH₃)₃ ] in an 85% yield. The alcohol 5 was then efficiently oxidized to the ketone with pyridinium chlorochromate (PCC). To a mixture of PCC (5.73 g, 0.027 mol), and 1.50 g powdered molecular sieves in 120 mL of CH₂ Cl₂ (stirred for 1 h at room temperature, then cooled in an ice-water bath) was added dropwise over 30 min the alcohol 5 (3.32 g, 0.011 mol) in 30 mL of CH₂ Cl₂. After stirring at room temperature for 3 h, the reaction mixture was suction-filtered directly through flash chromatography silica gel using CH₂ Cl₂ to remove excess PCC. The reaction mixture was then chromatographed on 100 g of flash chromatography silica gel using 25% EtOAc/hexane to afford 1.48 g (46%) of ketone 6. ¹ H NMR (CDCl₃, 300 MHz): δ4.80 (m, 1H, 2-H), 1.51 [m, 9H, C(CH₃)₃ ], 1.32 [m, 9H, C(CH₃)₃ ]. HRMS for C₁₅ H₂₆ NO₄ ; Calcd. M+H⁺ 299.1971. Found M+H⁺ 299.1979.

A solution of ketone 6 (1.37 g, 0.0046 mol) in THF (50 mL) was added at -78° C. to the anion generated from NaH (0.387 g, 0.00968 mol) and tetramethyl methylenediphosphonate (2.247 g, 0.068 mol) in dry THF. The reaction mixture was then stirred at room temperature for 2.5 h. The THF was removed at reduced pressure water bath temperature below 30° C.) to afford 3.77 g of residue. The residue showed two spots by thin-layer chromatography. Purification using 65 g flash chromatography silica gel and developed in 75% EtOAc/hexane afforded 0.625 g (36%) of the cis-protected isomer 7 and 0.710 g (39%) of the trans-protected isomer 8. HRMS for 7 C₁₈ H₃₃ N₂ O₆ P. Calcd. M+H⁺ 404.2154. Found M+H⁺ 404.2174. ¹ H NMR (CDCl₃, 300 MHz) δ5.45 (d, 1H, J=16 Hz HC═C), 4.75 (m, 1H, H-2), 3.69-3.80 (m, 6H, OCH₃), 1.49 [s, 9H, C(CH₃)₃ ], 1.33 [s, 9H, C(CH₃)₃ ].

Indeed, it seems that the amide proton of the 2-CONHR is very important in the transition state complex in directing the orientation of the phosphonate. The ketone analog 6 with the N-Boc protecting group and the t-butyl amide functionality also results in an olefin product mixture that is much more readily chromatographed, resulting in a higher and purer yield of Z-isomer 7. Removal of the protecting group was then accomplished by refluxing the phosphonate 7 and 8 in 6N HCl for 18 h to afford 9 and 10 respectively in quantitative yield. 9: EIMS (m/e): 437 (M.TMS₃ ⁺); ¹ H NMR (400 MHz, D₂ O) δ3.80 (dd, J=4, 12 Hz, 1H C_(2-H)), 5.75 (d, J=16 Hz, 1H, HC═C) 10: EIMS (m/e) 437 (M.TMS₃ ⁺); ¹ H NMR (400 MHz, D₂ O) 3.86 dd, J=4,12 Hz, 1H, C_(2H)), 5.78 (d, J=16 Hz, 1H HC═C). NOESY on 10 showed an NOE between the vinylic proton at δ5.78 and C-3H₃ at δ2.8.

EXAMPLE 2 Synthesis of 4-(phosphonomethylidene)-2-piperidinecarboxylic acid (E-isomer and Z-isomer) (Scheme 2)

Treatment of 4-piperidine ethylene ketal (14 g) with N'-tert-butyl-N,N-dimethylformamidine (38 g) in toluene (100 mL) at 100° C. for 24 hours afforded the formamidine ketal 11, b.p. 87° C./0.15 mm, in 86% yield. A solution of the formamidine 11 (12 g) in ether (240 mL) was treated with t-butyllithium (1.5M, 42 mL) in pentane, and the anion was alkylated with ethyl chloroformate (6.6 mL). Aqueous workup and evaporation of the solvent afforded the ester 12 (90% yield). A solution of the ester 12 (9.8 g) in MeOH (12 mL) and 10% KOH in 50% MeOH/H₂ O (11 mL) was refluxed for 1.5 hours, cooled to room temperature, neutralized to pH 8 with 1M HCl, and evaporated to dryness. Flash column chromatography on silica gel using ethyl acetate as solvent afforded the ketal (3.3 g, 41% yield). IR (CHCl₃):3434 (N-H), 1674 cm⁻¹ (amide). EIMS (m/z): 270 (M⁺). A solution of the ketal (3.2 g) in AcOH (28 mL) and H₂ O (28 mL) was heated at 80° C. for 2 hours, and the solvent was removed under reduced pressure. Crystallization from CH₂ Cl₂ --EtOAc yielded the ketone 13 (2.05 g, 75% yield). IR (CHCl₃): 3395 (N-H), 1725 (ketone), 1681 cm⁻ 1 (amide). EIMS (m/z): 226 (M⁺). A solution of ketone 13 (400 mg) in THF (20 mL) was added to the anion at -78° C., which was generated from NaH (98 mg) and tetramethyl methylenediphosphonate (0.90 g) in THF (12 mL). The bath was replaced with a water bath at room temperature, the mixture was stirred for 5 minutes, water was added (5 mL), and the solution was evaporated to dryness. Flash column chromatography on silica gel using CHCl₃ /acetone (2:8) gave the exocyclic Z-isomer 14 (102 mg) in 17% yield and the exocyclic E-isomer 15 (150 mg) in 25% yield. The 14 was crystallized from EtOAc/hexane; IR (CHCl₃): 3342 (N-H), 1679 cm⁻¹ (amide). EIMS (m/z): 332 (M⁺).

NMR (CDCl₃, 90 MHz): δ5.06 (dd, J=2 and 5 Hz, 1H, 2-H), 5.51 (d, J=16 Hz. 1H, HC═C). The exocyclic E-isomer 15 was crystallized from EtOAc/hexane; IR (CHCl₃): 3339 (N-H), 1678 cm⁻¹ (amide). EIMS (m/z): 332 (M⁺). NMR (CDCl₃, 90 MHz): δ4.99 (dd, J=1 and 5 Hz, 1H, 2-H), 5.60 (d, J=16 Hz, 1H, HC═C).

The Z-isomer 14 (55 mg) was heated with 6N HCl/H₂ O (3 mL) at 100° C. for 24 hours and evaporated to dryness. The residue was dissolved in MeOH (5 mL), treated with propylene oxide (0.5 mL), stirred for 0.5 hour, and evaporated to dryness. Purification by C₁₈ reverse-phase flash column chromatography, using water as solvent, gave compound 9 (52 mg, 70% yield). EIMS (m/z): 437 (M+ TMS₃ ⁺). NMR (D₂ O, 400 MHz): δ3.80 (dd, J=4 and 12 Hz, 1H, 2-H), 5.75 (d, J=16 Hz, 1H, HC═C).

The exocyclic E-isomer 15 (65 mg) was similarly treated with 6N HCl/H₂ O (3 mL). After workup and purification, a compound 10 (75% yield) was obtained with about 10% of isomer 9 by NMR. EIMS (m/z): 437 (M+TMS₃ ⁺). NMR (D₂ O, 400 MHz): δ3.86 (dd, J=4 and 12 Hz, 1H, 2-H), 5.78 (d, J=16 Hz, 1H, HC═C). The 9 (Z-isomer) and 10 (E-isomer) were differentiated, and their structures were predicted on the basis of NOESY and decoupling experiments.

The NOESY experiment on 10 showed an NOE between the vinylic proton at δ5.78 (d) and the 3H.sub.β at δ2.8. The assignment of 3-H.sub.β was confirmed by decoupling the 2-H proton (δ3.86), since the vicinal coupling of 3-H.sub.β to 2-H disappeared, leaving only the geminal coupling. Only the E-isomer would be expected to demonstrate this NOE between the vinylic proton and the 3-H, thus confirming that 10 is the E-isomer. In the case of the Z-isomer, there would be no coupling between the vinylic proton and 3-H.sub.β. However, a NOESY experiment on 9 showed the NOE between the vinylic proton and a proton at C-5, but no effect on C-3, consistent with the Z-assignment for 9.

EXAMPLE 3 Synthesis of ethyl 4-(phosphonomethylidene)-2-piperidine carboxylate (E-isomer and Z-isomer) (Scheme 3)

The intermediate 3 from Scheme 1 was required for the synthesis of ethyl 4-(phosphonomethylidene)-2-piperidinecarboxylate. The crude residue 3 from Scheme 1 (9.6 g, 0.046 mol) was dissolved in CH₂ Cl₂ (60 mL), anhydrous ethanol (30 mL), and diisopropylethylamine (8.01 mL). To this mixture was added di-tert-butyldicarbonate (9.5 g, 0.046 mol) in 5-mL portions every 10 minutes. The resultant mixture was stirred overnight at room temperature, then filtered through celite and concentrated in vacuo. The residue was extracted with ether-dichloromethane (2:1) and washed with 10% HCl. The organic layer was dried and evaporated to afford a light yellow clear liquid. The crude residue was purified by flash chromatography with EtOAc/hexane to afford the desired t-Boc-protected product (7.5 g, 60% yield). MS analysis showed the molecular ion peak at m/e 273. ¹ H NMR (90 MHz, CDCl₃): δ4.70 (m, 1H), 4.19 (m, 3H), 3.84 (m, 1H), 3.38 (m, 2H), 2.43 (m, 1H), 2.12 (m, 1H), 1.90 (m, 1H), 1.69 (m, 1H), 1.46 (s, 9H), 1.27 (t, 3H). To a mixture of PCC (11.19 g, 0.05 mol), and 11.19 g of powdered molecular sieves, in 100 mL of dichloromethane (stirred for 1 hour at room temperature, then cooled in an ice-water bath) was added dropwise, over 30 minutes, alcohol (6.0 g, 0.022 mol) in dichloromethane (50 mL). After this solution was stirred for 3 hours at room temperature, 500 mL of ether was added and the mixture was filtered through a pad of celite (bottom) and a pad of silica gel in sintered glass funnels. The filtrate was concentrated in vacuo; then 150 mL of ether was added to the residue and the solution was filtered through silica gel. This filtrate was concentrated in vacuo to afford the desired ketone 16 as a yellow-green oil (5.70 g, 95% yield).

A solution of ketone 16 (4.3 g, 0.016 mol) in THF (60 mL) was added at -78° C. to the anion, which was generated from NaH (0.652 g, 0.027 mol) and tetramethyl methylene diphosphonate (6.31 g, 0.027 mol) in THF. The reaction mixture was stirred at room temperature for 1 hour. After that, water was added and the product extracted with chloroform. The chloroform layer was dried, filtered, and evaporated to afford a colorless viscous oil (4.5 g, 75%). The ¹ H NMR (400 MHz) clearly showed that the oil consisted of the E-isomer 18 (85%) and the Z-isomer 17 (15%). The Z-isomer and the E-isomer were differentiated and their structures predicted on the basis of NOESY and decoupling experiments. The NOESY experiment on this mixture showed an NOE between the vinylic proton and the 3-H.sub.β. The assignment of 3-H.sub.β was confirmed by decoupling the 2-H, because the vicinal coupling of 3-H.sub.β to 2-H disappeared, leaving only the geminal coupling. The mixture of protected piperidine ester (17 and 18) (100 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After that the solvent was evaporated to afford an oil, which was triturated with ether. To the residue were added dichloromethane (50 mL) and saturated sodium bicarbonate solution; the organic layer was dried, filtered, and evaporated to give a mixture of deprotected ethylester 19 and 20 as a thick oil (70 mg, 95% yield).

To the dichloromethane solution (10 mL) of the phosphonomethylidene ester 19 and 20 (138 mg, 0.5 mmol) was added bromotrimethylsilane (4 eq., 0.300 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and methanol (2 mL) was added to hydrolyze the phosphonosilyl ester to give a residue. The residue was dissolved in a minimal amount of ethanol, and ether was added with HCl to give a light yellow powder. This powder was dissolved in ethanol, and propylene oxide (1 mL) was added to precipitate the mixture of phosphonic acid 21 and 22 (2:8 mixture) as a white powder (100 mg). EIMS (m/z): 393 (M+TMS₂)

¹ H NMR (D₂ O, 400 MHz): δ1.28 (t, 3H, CH₂), 2.5 (m, 1H, 6-H.sub.α), 2.65 (bt, 1H, 3-H.sub.α), 2.95 (dd, 1H, 3-H.sub.β), 3.12 (tt, 1H, 5-H.sub.α), 3.30 (dd, 1H, 6-H.sub.β), 3.65 (bt, 1H, 5-H.sub.β), 4.2 (dd, J=4 and 12 MHz, 1H, 2-H), 4.32 (q, 3H, CH₃), 5.80 (d, J=16 Hz, 1H, HC═C).

In Vitro Binding Assay using [³ H]CGS-19755 as the Radioligand at the NMDA Receptor Site

Compounds such as CGS-19755 (cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid) have been shown to be high-affinity antagonists at the NMDA recognition site (Lehman et al., 1988; Murphy et al., 1987). The compounds of the invention were tested for their ability to inhibit [³ H]CGS-19755 binding. Semipurified synaptic membranes were prepared according to the method of Bristow et al. (1986) with minor modifications. Adult male Sprague-Dawley rats were decapitated, and the forebrains were removed, weighed and homogenized in 20 volumes of 0.32M sucrose. The homogenate was centrifuged at 27,000×G for 15 minutes. The pellet was resuspended in 20 volumes of distilled water followed by centrifugation at 8000×G for minutes. Both the supernatant and the buffy coat layer, removed with 5 mM Tris-Cl (2 mL), pH 7.8, were pooled and centrifuged at 27,000×G for 15 minutes. The supernatant was removed and the pellet was covered with a small amount of 5 mM Tris-HCl and stored at -20° C. for least 18 hours. Membranes were then washed four times in 50 mM Tris-citrate, pH 7.1, and finally resuspended in the same buffer. This suspension was used for the binding assay immediately or frozen for subsequent use.

Aliquots of membranes (800 μl) were incubated with 10 nM [³ H]CGS-19755 (100 μl) and varying concentrations of the test compounds (100 μl) for 15 minutes at 4° C. Then a filtration assay was used. The samples were filtered over glass fiber filters using a Brandel Cell Harvester. The filters were left overnight in 5 mL scintillation cocktail before counting.

Table 1 summarizes the results of the in vitro binding studies using [³ H]CGS-19755 as the radioligand at the NMDA receptor site.

Ki values were calculated from the equation: ##EQU1##

                  TABLE 1                                                          ______________________________________                                         In Vitro Binding Assay at the NMDA Receptor Site                                                     Ki (μM)                                               Compound              [.sup.3 H]CGS19755                                       ______________________________________                                         CGS-19755(cis-4-(phosphonomethyl)-                                                                   0.112                                                    2-piperidinecarboxylic acid)                                                   E-4-(phosphonomethylidene)-2-                                                                        0.59                                                     piperidinecarboxylic acid                                                      ______________________________________                                    

In Vivo Protection in the Mouse Against NMDA-Induced Lethality

According to the method described by Ferkany et al. (1988), the test compounds were administered ip to four male Swiss-Webster mice (26-34 g) each, following 30 minutes later, 200 mg/kg of NMDA was administered to the mice each. The LD₅₀ of NMDA was found to be 164 mg/kg, and approximately 90% of the mice died at 200 mg/kg. Those compounds that protected three or more of the mice at any of the doses were evaluated further by determining the ED₅₀ values using three or more doses with the eight mice per dose. The ED₅₀ was estimated by the method of Litchfield and Wilcoxin (1949). Water-soluble compounds were dissolved in distilled water and administered in a volume of 10 mL/kg. Water-insoluble compounds were suspended in an aqueous solution of 0.5% methyl cellulose and administered in a volume of 20 mL/kg.

Table 2 also summarizes the results of this test.

                  TABLE 2                                                          ______________________________________                                         NMDA-Induced Lethality Test in the Mouse                                                                 Confidence                                           Compound       PD.sub.50 (mg/kg)                                                                         Limits     Slope                                     ______________________________________                                         CGS-19755 (cis-4-                                                                             2.0        1.2-3.6    2.46                                      (phosphonomethyl)-                                                             2-piperidine-                                                                  carboxylic acid)                                                               E-4-(phosphonomethyl-                                                                         1.1        0.5-2.2    1.96                                      idene-2-piperidine-                                                            carboxylic acid                                                                ______________________________________                                    

    ______________________________________                                         Representative Composition A                                                   An oral suspension is prepared having the                                      following composition                                                          Ingredients                                                                    ______________________________________                                         Active ingredient    0.1        g                                              fumaric acid         0.5        g                                              sodium chloride      2.0        g                                              methyl paraben       0.1        g                                              granulated sugar     25.5       g                                              sorbitol (70% solution)                                                                             12.85      g                                              Veegum K (Vanderbilt Co.)                                                                           1.0        g                                              flavoring            0.035      mL                                             colorings            0.5        mg                                             distilled water      q.s. to 100                                                                               mL                                             ______________________________________                                         Representative Composition B                                                                        Quantity per                                              Ingredients          tablet (mg)                                               ______________________________________                                         active ingredient    25                                                        cornstarch           20                                                        lactose, spray-dried 153                                                       magnesium stearate    2                                                        ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into single-scored tablets.

EXAMPLES 0 and 4-1125

The reactions of Examples 1 and 2 and 3 are repeated varying the feedstocks as set forth in the preparation section. This gives rise to the following compounds of the invention:

    __________________________________________________________________________     Example        X     n             R.sub.1   R.sub.2  R.sub.3                  __________________________________________________________________________     1.2            CH    0             H         H        H                        0              CH    0             H         H        Methyl                   3              CH    0             H         H        Ethyl                    4              CH    0             H         H        Propyl                   5              CH    0             H         H        Butyl                                    ##STR8##                                                                            0             H         Methyl   Methyl                   7                                                                                              ##STR9##                                                                            0             H         Methyl   Ethyl                    8                                                                                              ##STR10##                                                                           0             H         Methyl   Propyl                   9                                                                                              ##STR11##                                                                           0             H         Methyl   Butyl                    10                                                                                             ##STR12##                                                                           0             H         Ethyl    Ethyl                    11             CH    0             H         Ethyl    Propyl                   12                                                                                             ##STR13##                                                                           0             H         Ethyl    Butyl                    13                                                                                             ##STR14##                                                                           0             H         Propyl   Propyl                   14             CH    0             H         Propyl   Butyl                    15             CH    0             H         Butyl    Butyl                    16                                                                                             ##STR15##                                                                           0             H         H        H                        17                                                                                             ##STR16##                                                                           0             H         H        Methyl                   18                                                                                             ##STR17##                                                                           0             H         H        Ethyl                    19                                                                                             ##STR18##                                                                           0             H         H        Propyl                   20                                                                                             ##STR19##                                                                           0             H         H        Butyl                    21                                                                                             ##STR20##                                                                           0             H         Methyl   Methyl                   22             CF    0             H         Methyl   Ethyl                    23                                                                                             ##STR21##                                                                           0             H         Methyl   Propyl                   24                                                                                             ##STR22##                                                                           0             H         Methyl   Butyl                    25                                                                                             ##STR23##                                                                           0             H         Ethyl    Ethyl                    26                                                                                             ##STR24##                                                                           0             H         Ethyl    Propyl                   27                                                                                             ##STR25##                                                                           0             H         Ethyl    Butyl                    28                                                                                             ##STR26##                                                                           0             H         Propyl   Propyl                   29                                                                                             ##STR27##                                                                           0             H         Propyl   Butyl                    30                                                                                             ##STR28##                                                                           0             H         Butyl    Butyl                    31             NO    0             H         H        H                        32             NO    0             H         H        Methyl                   33             NO    0             H         H        Ethyl                    34             NO    0             H         H        Propyl                   35             NO    0             H         H        Butyl                    36             NO    0             H         Methyl   Methyl                   37             NO    0             H         Methyl   Ethyl                    38             NO    0             H         Methyl   Propyl                   39             NO    0             H         Methyl   Butyl                    40             NO    0             H         Ethyl    Ethyl                    41             NO    0             H         Ethyl    Propyl                   42             NO    0             H         Ethyl    Butyl                    43             NO    0             H         Propyl   Propyl                   44             NO    0             H         Propyl   Butyl                    45             NO    0             H         Butyl    Butyl                    46             CH    1             H         H        H                        47             CH    1             H         H        Methyl                   48             CH    1             H         H        Ethyl                    49             CH    1             H         H        Propyl                   50                                                                                             ##STR29##                                                                           1             H         H        Butyl                    51                                                                                             ##STR30##                                                                           1             H         Methyl   Methyl                   52                                                                                             ##STR31##                                                                           1             H         Methyl   Ethyl                    53             CH    1             H         Methyl   Propyl                   54                                                                                             ##STR32##                                                                           1             H         Methyl   Butyl                    55                                                                                             ##STR33##                                                                           1             H         Ethyl    Ethyl                    56                                                                                             ##STR34##                                                                           1             H         Ethyl    Propyl                   57             CH    1             H         Ethyl    Butyl                    58                                                                                             ##STR35##                                                                           1             H         Propyl   Propyl                   59                                                                                             ##STR36##                                                                           1             H         Propyl   Butyl                    60                                                                                             ##STR37##                                                                           1             H         Butyl    Butyl                    61                                                                                             ##STR38##                                                                           1             H         H        H                        62                                                                                             ##STR39##                                                                           1             H         H        Methyl                   63                                                                                             ##STR40##                                                                           1             H         H        Ethyl                    64                                                                                             ##STR41##                                                                           1             H         H        Propyl                   65                                                                                             ##STR42##                                                                           1             H         H        Butyl                    66                                                                                             ##STR43##                                                                           1             H         Methyl   Methyl                   67                                                                                             ##STR44##                                                                           1             H         Methyl   Ethyl                    68                                                                                             ##STR45##                                                                           1             H         Methyl   Propyl                   69                                                                                             ##STR46##                                                                           1             H         Methyl   Butyl                    70                                                                                             ##STR47##                                                                           1             H         Ethyl    Ethyl                    71                                                                                             ##STR48##                                                                           1             H         Ethyl    Propyl                   72                                                                                             ##STR49##                                                                           1             H         Ethyl    Butyl                    73                                                                                             ##STR50##                                                                           1             H         Propyl   Propyl                   74                                                                                             ##STR51##                                                                           1             H         Propyl   Butyl                    75                                                                                             ##STR52##                                                                           1             H         Butyl    Butyl                    76             NO    1             H         H        H                        77             NO    1             H         H        Methyl                   78             NO    1             H         H        Ethyl                    79             NO    1             H         H        Propyl                   80             NO    1             H         H        Butyl                    81             NO    1             H         Methyl   Methyl                   82             NO    1             H         Methyl   Ethyl                    83             NO    1             H         Methyl   Propyl                   84             NO    1             H         Methyl   Butyl                    85             NO    1             H         Ethyl    Ethyl                    86             NO    1             H         Ethyl    Propyl                   87             NO    1             H         Ethyl    Butyl                    88             NO    1             H         Propyl   Propyl                   89             NO    1             H         Propyl   Butyl                    90             NO    1             H         Butyl    Butyl                    91             CH    2             H         H        H                        92             CH    2             H         H        Methyl                   93             CH    2             H         H        Ethyl                    94                                                                                             ##STR53##                                                                           2             H         H        Propyl                   95                                                                                             ##STR54##                                                                           2             H         H        Butyl                    96                                                                                             ##STR55##                                                                           2             H         Methyl   Methyl                   97                                                                                             ##STR56##                                                                           2             H         Methyl   Ethyl                    98                                                                                             ##STR57##                                                                           2             H         Methyl   Propyl                   99                                                                                             ##STR58##                                                                           2             H         Methyl   Butyl                    100                                                                                            ##STR59##                                                                           2             H         Ethyl    Ethyl                    101                                                                                            ##STR60##                                                                           2             H         Ethyl    Propyl                   102                                                                                            ##STR61##                                                                           2             H         Ethyl    Butyl                    103                                                                                            ##STR62##                                                                           2             H         Propyl   Propyl                   104            CH    2             H         Propyl   Butyl                    105            CH    2             H         Butyl    Butyl                    106                                                                                            ##STR63##                                                                           2             H         H        H                        107                                                                                            ##STR64##                                                                           2             H         H        Methyl                   108                                                                                            ##STR65##                                                                           2             H         H        Ethyl                    109                                                                                            ##STR66##                                                                           2             H         H        Propyl                   110                                                                                            ##STR67##                                                                           2             H         H        Butyl                    111                                                                                            ##STR68##                                                                           2             H         Methyl   Methyl                   112                                                                                            ##STR69##                                                                           2             H         Methyl   Ethyl                    113                                                                                            ##STR70##                                                                           2             H         Methyl   Propyl                   114                                                                                            ##STR71##                                                                           2             H         Methyl   Butyl                    115                                                                                            ##STR72##                                                                           2             H         Ethyl    Ethyl                    116                                                                                            ##STR73##                                                                           2             H         Ethyl    Propyl                   117                                                                                            ##STR74##                                                                           2             H         Ethyl    Butyl                    118                                                                                            ##STR75##                                                                           2             H         Propyl   Propyl                   119                                                                                            ##STR76##                                                                           2             H         Propyl   Butyl                    120                                                                                            ##STR77##                                                                           2             H         Butyl    Butyl                    121            NO    2             H         H        H                        122            NO    2             H         H        Methyl                   123            NO    2             H         H        Ethyl                    124            NO    2             H         H        Propyl                   125            NO    2             H         H        Butyl                    126            NO    2             H         Methyl   Methyl                   127            NO    2             H         Methyl   Ethyl                    128            NO    2             H         Methyl   Propyl                   129            NO    2             H         Methyl   Butyl                    130            NO    2             H         Ethyl    Ethyl                    131            NO    2             H         Ethyl    Propyl                   132            NO    2             H         Ethyl    Butyl                    133            NO    2             H         Propyl   Propyl                   134            NO    2             H         Propyl   Butyl                    135            NO    2             H         Butyl    Butyl                    136            CH    3             H         H        H                        137            CH    3             H         H        Methyl                   138            CH    3             H         H        Ethyl                    139                                                                                            ##STR78##                                                                           3             H         H        Propyl                   140                                                                                            ##STR79##                                                                           3             H         H        Butyl                    141                                                                                            ##STR80##                                                                           3             H         Methyl   Methyl                   142                                                                                            ##STR81##                                                                           3             H         Methyl   Ethyl                    143                                                                                            ##STR82##                                                                           3             H         Methyl   Propyl                   144                                                                                            ##STR83##                                                                           3             H         Methyl   Butyl                    145                                                                                            ##STR84##                                                                           3             H         Ethyl    Ethyl                    146                                                                                            ##STR85##                                                                           3             H         Ethyl    Propyl                   147            CH    3             H         Ethyl    Butyl                    148                                                                                            ##STR86##                                                                           3             H         Propyl   Propyl                   149                                                                                            ##STR87##                                                                           3             H         Propyl   Butyl                    150                                                                                            ##STR88##                                                                           3             H         Butyl    Butyl                    151                                                                                            ##STR89##                                                                           3             H         H        H                        152                                                                                            ##STR90##                                                                           3             H         H        Methyl                   153                                                                                            ##STR91##                                                                           3             H         H        Ethyl                    154                                                                                            ##STR92##                                                                           3             H         H        Propyl                   155                                                                                            ##STR93##                                                                           3             H         H        Butyl                    156                                                                                            ##STR94##                                                                           3             H         Methyl   Methyl                   157                                                                                            ##STR95##                                                                           3             H         Methyl   Ethyl                    158                                                                                            ##STR96##                                                                           3             H         Methyl   Propyl                   159                                                                                            ##STR97##                                                                           3             H         Methyl   Butyl                    160                                                                                            ##STR98##                                                                           3             H         Ethyl    Ethyl                    161                                                                                            ##STR99##                                                                           3             H         Ethyl    Propyl                   162                                                                                            ##STR100##                                                                          3             H         Ethyl    Butyl                    163                                                                                            ##STR101##                                                                          3             H         Propyl   Propyl                   164                                                                                            ##STR102##                                                                          3             H         Propyl   Butyl                    165                                                                                            ##STR103##                                                                          3             H         Butyl    Butyl                    166            NO    3             H         H        H                        167            NO    3             H         H        Methyl                   168            NO    3             H         H        Ethyl                    169            NO    3             H         H        Propyl                   170            NO    3             H         H        Butyl                    171            NO    3             H         Methyl   Methyl                   172            NO    3             H         Methyl   Ethyl                    173            NO    3             H         Methyl   Propyl                   174            NO    3             H         Methyl   Butyl                    175            NO    3             H         Ethyl    Ethyl                    176            NO    3             H         Ethyl    Propyl                   177            NO    3             H         Ethyl    Butyl                    178            NO    3             H         Propyl   Propyl                   179            NO    3             H         Propyl   Butyl                    180            NO    3             H         Butyl    Butyl                    181            CH    4             H         H        H                        182                                                                                            ##STR104##                                                                          4             H         H        Methyl                   183                                                                                            ##STR105##                                                                          4             H         H        Ethyl                    184            CH    4             H         H        Propyl                   185                                                                                            ##STR106##                                                                          4             H         H        Butyl                    186                                                                                            ##STR107##                                                                          4             H         Methyl   Methyl                   187                                                                                            ##STR108##                                                                          4             H         Methyl   Ethyl                    188                                                                                            ##STR109##                                                                          4             H         Methyl   Propyl                   189                                                                                            ##STR110##                                                                          4             H         Methyl   Butyl                    190                                                                                            ##STR111##                                                                          4             H         Ethyl    Ethyl                    191                                                                                            ##STR112##                                                                          4             H         Ethyl    Propyl                   192                                                                                            ##STR113##                                                                          4             H         Ethyl    Butyl                    193                                                                                            ##STR114##                                                                          4             H         Propyl   Propyl                   194                                                                                            ##STR115##                                                                          4             H         Propyl   Butyl                    195                                                                                            ##STR116##                                                                          4             H         Butyl    Butyl                    196                                                                                            ##STR117##                                                                          4             H         H        H                        197                                                                                            ##STR118##                                                                          4             H         H        Methyl                   198                                                                                            ##STR119##                                                                          4             H         H        Ethyl                    199                                                                                            ##STR120##                                                                          4             H         H        Propyl                   200                                                                                            ##STR121##                                                                          4             H         H        Butyl                    201                                                                                            ##STR122##                                                                          4             H         Methyl   Methyl                   202                                                                                            ##STR123##                                                                          4             H         Methyl   Ethyl                    203                                                                                            ##STR124##                                                                          4             H         Methyl   Propyl                   204                                                                                            ##STR125##                                                                          4             H         Methyl   Butyl                    205                                                                                            ##STR126##                                                                          4             H         Ethyl    Ethyl                    206                                                                                            ##STR127##                                                                          4             H         Ethyl    Propyl                   207                                                                                            ##STR128##                                                                          4             H         Ethyl    Butyl                    208                                                                                            ##STR129##                                                                          4             H         Propyl   Propyl                   209                                                                                            ##STR130##                                                                          4             H         Propyl   Butyl                    210                                                                                            ##STR131##                                                                          4             H         Butyl    Butyl                    211            NO    4             H         H        H                        212            NO    4             H         H        Methyl                   213            NO    4             H         H        Ethyl                    214            NO    4             H         H        Propyl                   215            NO    4             H         H        Butyl                    216            NO    4             H         Methyl   Methyl                   217            NO    4             H         Methyl   Ethyl                    218            NO    4             H         Methyl   Propyl                   219            NO    4             H         Methyl   Butyl                    220            NO    4             H         Ethyl    Ethyl                    221            NO    4             H         Ethyl    Propyl                   222            NO    4             H         Ethyl    Butyl                    223            NO    4             H         Propyl   Propyl                   224            NO    4             H         Propyl   Butyl                    225            NO    4             H         Butyl    Butyl                    226            CH    0             Methyl    H        H                        227            CH    0             Methyl    H        Methyl                   228            CH    0             Methyl    H        Ethyl                    229            CH    0             Methyl    H        Propyl                   230            CH    0             Methyl    H        Butyl                    231            CH    0             Methyl    Methyl   Methyl                   232                                                                                            ##STR132##                                                                          0             Methyl    Methyl   Ethyl                    233                                                                                            ##STR133##                                                                          0             Methyl    Methyl   Propyl                   234            CH    0             Methyl    Methyl   Butyl                    235            CH    0             Methyl    Ethyl    Ethyl                    236                                                                                            ##STR134##                                                                          0             Methyl    Ethyl    Propyl                   237                                                                                            ##STR135##                                                                          0             Methyl    Ethyl    Butyl                    238                                                                                            ##STR136##                                                                          0             Methyl    Propyl   Propyl                   239                                                                                            ##STR137##                                                                          0             Methyl    Propyl   Butyl                    240                                                                                            ##STR138##                                                                          0             Methyl    Butyl    Butyl                    241                                                                                            ##STR139##                                                                          0             Methyl    H        H                        242                                                                                            ##STR140##                                                                          0             Methyl    H        Methyl                   243                                                                                            ##STR141##                                                                          0             Methyl    H        Ethyl                    244                                                                                            ##STR142##                                                                          0             Methyl    H        Propyl                   245                                                                                            ##STR143##                                                                          0             Methyl    H        Butyl                    246                                                                                            ##STR144##                                                                          0             Methyl    Methyl   Methyl                   247                                                                                            ##STR145##                                                                          0             Methyl    Methyl   Ethyl                    248                                                                                            ##STR146##                                                                          0             Methyl    Methyl   Propyl                   249                                                                                            ##STR147##                                                                          0             Methyl    Methyl   Butyl                    250                                                                                            ##STR148##                                                                          0             Methyl    Ethyl    Ethyl                    251                                                                                            ##STR149##                                                                          0             Methyl    Ethyl    Propyl                   252                                                                                            ##STR150##                                                                          0             Methyl    Ethyl    Butyl                    253                                                                                            ##STR151##                                                                          0             Methyl    Propyl   Propyl                   254                                                                                            ##STR152##                                                                          0             Methyl    Propyl   Butyl                    255                                                                                            ##STR153##                                                                          0             Methyl    Butyl    Butyl                    256                                                                                            ##STR154##                                                                          0             Ethyl     H        H                        257                                                                                            ##STR155##                                                                          0             Ethyl     H        Methyl                   258                                                                                            ##STR156##                                                                          0             Ethyl     H        Ethyl                    259                                                                                            ##STR157##                                                                          0             Ethyl     H        Propyl                   260                                                                                            ##STR158##                                                                          0             Ethyl     H        Butyl                    261                                                                                            ##STR159##                                                                          0             Ethyl     Methyl   Methyl                   262            CH    0             Ethyl     Methyl   Ethyl                    263                                                                                            ##STR160##                                                                          0             Ethyl     Methyl   Propyl                   264                                                                                            ##STR161##                                                                          0             Ethyl     Methyl   Butyl                    265                                                                                            ##STR162##                                                                          0             Ethyl     Ethyl    Ethyl                    266                                                                                            ##STR163##                                                                          0             Ethyl     Ethyl    Propyl                   267                                                                                            ##STR164##                                                                          0             Ethyl     Ethyl    Butyl                    268                                                                                            ##STR165##                                                                          0             Ethyl     Propyl   Propyl                   269                                                                                            ##STR166##                                                                          0             Ethyl     Propyl   Butyl                    270                                                                                            ##STR167##                                                                          0             Ethyl     Butyl    Butyl                    271            CF    0             Ethyl     H        H                        272            CF    0             Ethyl     H        Methyl                   273            CF    0             Ethyl     H        Ethyl                    274                                                                                            ##STR168##                                                                          0             Ethyl     H        Propyl                   275                                                                                            ##STR169##                                                                          0             Ethyl     H        Butyl                    276                                                                                            ##STR170##                                                                          0             Ethyl     Methyl   Methyl                   277                                                                                            ##STR171##                                                                          0             Ethyl     Methyl   Ethyl                    278                                                                                            ##STR172##                                                                          0             Ethyl     Methyl   Propyl                   279                                                                                            ##STR173##                                                                          0             Ethyl     Methyl   Butyl                    280                                                                                            ##STR174##                                                                          0             Ethyl     Ethyl    Ethyl                    281                                                                                            ##STR175##                                                                          0             Ethyl     Ethyl    Propyl                   282                                                                                            ##STR176##                                                                          0             Ethyl     Ethyl    Butyl                    283                                                                                            ##STR177##                                                                          0             Ethyl     Propyl   Propyl                   284                                                                                            ##STR178##                                                                          0             Ethyl     Propyl   Butyl                    285            CF    0             Ethyl     Butyl    Butyl                    286            CH    0             Propyl    H        H                        287                                                                                            ##STR179##                                                                          0             Propyl    H        Methyl                   288                                                                                            ##STR180##                                                                          0             Propyl    H        Ethyl                    289                                                                                            ##STR181##                                                                          0             Propyl    H        Propyl                   290                                                                                            ##STR182##                                                                          0             Propyl    H        Butyl                    291                                                                                            ##STR183##                                                                          0             Propyl    Methyl   Methyl                   292                                                                                            ##STR184##                                                                          0             Propyl    Methyl   Ethyl                    293                                                                                            ##STR185##                                                                          0             Propyl    Methyl   Propyl                   294                                                                                            ##STR186##                                                                          0             Propyl    Methyl   Butyl                    295                                                                                            ##STR187##                                                                          0             Propyl    Ethyl    Ethyl                    296                                                                                            ##STR188##                                                                          0             Propyl    Ethyl    Propyl                   297                                                                                            ##STR189##                                                                          0             Propyl    Ethyl    Butyl                    298                                                                                            ##STR190##                                                                          0             Propyl    Propyl   Propyl                   299                                                                                            ##STR191##                                                                          0             Propyl    Propyl   Butyl                    300                                                                                            ##STR192##                                                                          0             Propyl    Butyl    Butyl                    301                                                                                            ##STR193##                                                                          0             Propyl    H        H                        302                                                                                            ##STR194##                                                                          0             Propyl    H        Methyl                   303                                                                                            ##STR195##                                                                          0             Propyl    H        Ethyl                    304                                                                                            ##STR196##                                                                          0             Propyl    H        Propyl                   305                                                                                            ##STR197##                                                                          0             Propyl    H        Butyl                    306                                                                                            ##STR198##                                                                          0             Propyl    Methyl   Methyl                   307            CF    0             Propyl    Methyl   Ethyl                    308            CF    0             Propyl    Methyl   Propyl                   309            CF    0             Propyl    Methyl   Butyl                    310            CF    0             Propyl    Ethyl    Ethyl                    311            CF    0             Propyl    Ethyl    Propyl                   312                                                                                            ##STR199##                                                                          0             Propyl    Ethyl    Butyl                    313                                                                                            ##STR200##                                                                          0             Propyl    Propyl   Propyl                   314                                                                                            ##STR201##                                                                          0             Propyl    Propyl   Butyl                    315                                                                                            ##STR202##                                                                          0             Propyl    Butyl    Butyl                    316            CH    0             Butyl     H        H                        317            CH    0             Butyl     H        Methyl                   318                                                                                            ##STR203##                                                                          0             Butyl     H        Ethyl                    319                                                                                            ##STR204##                                                                          0             Butyl     H        Propyl                   320                                                                                            ##STR205##                                                                          0             Butyl     H        Butyl                    321                                                                                            ##STR206##                                                                          0             Butyl     Methyl   Methyl                   322                                                                                            ##STR207##                                                                          0             Butyl     Methyl   Ethyl                    323                                                                                            ##STR208##                                                                          0             Butyl     Methyl   Propyl                   324                                                                                            ##STR209##                                                                          0             Butyl     Methyl   Butyl                    325                                                                                            ##STR210##                                                                          0             Butyl     Ethyl    Ethyl                    326                                                                                            ##STR211##                                                                          0             Butyl     Ethyl    Propyl                   327                                                                                            ##STR212##                                                                          0             Butyl     Ethyl    Butyl                    328                                                                                            ##STR213##                                                                          0             Butyl     Propyl   Propyl                   329                                                                                            ##STR214##                                                                          0             Butyl     Propyl   Butyl                    330                                                                                            ##STR215##                                                                          0             Butyl     Butyl    Butyl                    331                                                                                            ##STR216##                                                                          0             Butyl     H        H                        332                                                                                            ##STR217##                                                                          0             Butyl     H        Methyl                   333                                                                                            ##STR218##                                                                          0             Butyl     H        Ethyl                    334                                                                                            ##STR219##                                                                          0             Butyl     H        Propyl                   335                                                                                            ##STR220##                                                                          0             Butyl     H        Butyl                    336                                                                                            ##STR221##                                                                          0             Butyl     Methyl   Methyl                   337                                                                                            ##STR222##                                                                          0             Butyl     Methyl   Ethyl                    338                                                                                            ##STR223##                                                                          0             Butyl     Methyl   Propyl                   339                                                                                            ##STR224##                                                                          0             Butyl     Methyl   Butyl                    340                                                                                            ##STR225##                                                                          0             Butyl     Ethyl    Ethyl                    341                                                                                            ##STR226##                                                                          0             Butyl     Ethyl    Propyl                   342                                                                                            ##STR227##                                                                          0             Butyl     Ethyl    Butyl                    343                                                                                            ##STR228##                                                                          0             Butyl     Propyl   Propyl                   344                                                                                            ##STR229##                                                                          0             Butyl     Propyl   Butyl                    345                                                                                            ##STR230##                                                                          0             Butyl     Butyl    Butyl                    346                                                                                            ##STR231##                                                                          1             Methyl    H        H                        347                                                                                            ##STR232##                                                                          1             Methyl    H        Methyl                   348                                                                                            ##STR233##                                                                          1             Methyl    H        Ethyl                    349                                                                                            ##STR234##                                                                          1             Methyl    H        Propyl                   350                                                                                            ##STR235##                                                                          1             Methyl    H        Butyl                    351                                                                                            ##STR236##                                                                          1             Methyl    Methyl   Methyl                   352                                                                                            ##STR237##                                                                          1             Methyl    Methyl   Ethyl                    353                                                                                            ##STR238##                                                                          1             Methyl    Methyl   Propyl                   354                                                                                            ##STR239##                                                                          1             Methyl    Methyl   Butyl                    355                                                                                            ##STR240##                                                                          1             Methyl    Ethyl    Ethyl                    356                                                                                            ##STR241##                                                                          1             Methyl    Ethyl    Propyl                   357                                                                                            ##STR242##                                                                          1             Methyl    Ethyl    Butyl                    358                                                                                            ##STR243##                                                                          1             Methyl    Propyl   Propyl                   359                                                                                            ##STR244##                                                                          1             Methyl    Propyl   Butyl                    360                                                                                            ##STR245##                                                                          1             Methyl    Butyl    Butyl                    361            CF    1             Methyl    H        H                        362            CF    1             Methyl    H        Methyl                   363            CF    1             Methyl    H        Ethyl                    364            CF    1             Methyl    H        Propyl                   365            CF    1             Methyl    H        Butyl                    366                                                                                            ##STR246##                                                                          1             Methyl    Methyl   Methyl                   367            CF    1             Methyl    Methyl   Ethyl                    368            CF    1             Methyl    Methyl   Propyl                   369            CF    1             Methyl    Methyl   Butyl                    370                                                                                            ##STR247##                                                                          1             Methyl    Ethyl    Ethyl                    371                                                                                            ##STR248##                                                                          1             Methyl    Ethyl    Propyl                   372                                                                                            ##STR249##                                                                          1             Methyl    Ethyl    Butyl                    373            CF    1             Methyl    Propyl   Propyl                   374                                                                                            ##STR250##                                                                          1             Methyl    Propyl   Butyl                    375                                                                                            ##STR251##                                                                          1             Methyl    Butyl    Butyl                    376                                                                                            ##STR252##                                                                          1             Ethyl     H        H                        377                                                                                            ##STR253##                                                                          1             Ethyl     H        Methyl                   378                                                                                            ##STR254##                                                                          1             Ethyl     H        Ethyl                    379                                                                                            ##STR255##                                                                          1             Ethyl     H        Propyl                   380                                                                                            ##STR256##                                                                          1             Ethyl     H        Butyl                    381                                                                                            ##STR257##                                                                          1             Ethyl     Methyl   Methyl                   382                                                                                            ##STR258##                                                                          1             Ethyl     Methyl   Ethyl                    383                                                                                            ##STR259##                                                                          1             Ethyl     Methyl   Propyl                   384                                                                                            ##STR260##                                                                          1             Ethyl     Methyl   Butyl                    385                                                                                            ##STR261##                                                                          1             Ethyl     Ethyl    Ethyl                    386                                                                                            ##STR262##                                                                          1             Ethyl     Ethyl    Propyl                   387                                                                                            ##STR263##                                                                          1             Ethyl     Ethyl    Butyl                    388                                                                                            ##STR264##                                                                          1             Ethyl     Propyl   Propyl                   389                                                                                            ##STR265##                                                                          1             Ethyl     Propyl   Butyl                    390                                                                                            ##STR266##                                                                          1             Ethyl     Butyl    Butyl                    391                                                                                            ##STR267##                                                                          1             Ethyl     H        H                        392            CF    1             Ethyl     H        Methyl                   393                                                                                            ##STR268##                                                                          1             Ethyl     H        Ethyl                    394                                                                                            ##STR269##                                                                          1             Ethyl     H        Propyl                   395                                                                                            ##STR270##                                                                          1             Ethyl     H        Butyl                    396            CF    1             Ethyl     Methyl   Methyl                   397            CF    1             Ethyl     Methyl   Ethyl                    398            CF    1             Ethyl     Methyl   Propyl                   399                                                                                            ##STR271##                                                                          1             Ethyl     Methyl   Butyl                    400                                                                                            ##STR272##                                                                          1             Ethyl     Ethyl    Ethyl                    401                                                                                            ##STR273##                                                                          1             Ethyl     Ethyl    Propyl                   402                                                                                            ##STR274##                                                                          1             Ethyl     Ethyl    Butyl                    403            CF    1             Ethyl     Propyl   Propyl                   404                                                                                            ##STR275##                                                                          1             Ethyl     Propyl   Butyl                    405                                                                                            ##STR276##                                                                          1             Ethyl     Butyl    Butyl                    406            CH    1             Propyl    H        H                        407            CH    1             Propyl    H        Methyl                   408                                                                                            ##STR277##                                                                          1             Propyl    H        Ethyl                    409                                                                                            ##STR278##                                                                          1             Propyl    H        Propyl                   410                                                                                            ##STR279##                                                                          1             Propyl    H        Butyl                    411                                                                                            ##STR280##                                                                          1             Propyl    Methyl   Methyl                   412                                                                                            ##STR281##                                                                          1             Propyl    Methyl   Ethyl                    413                                                                                            ##STR282##                                                                          1             Propyl    Methyl   Propyl                   414                                                                                            ##STR283##                                                                          1             Propyl    Methyl   Butyl                    415                                                                                            ##STR284##                                                                          1             Propyl    Ethyl    Ethyl                    416                                                                                            ##STR285##                                                                          1             Propyl    Ethyl    Propyl                   417                                                                                            ##STR286##                                                                          1             Propyl    Ethyl    Butyl                    418                                                                                            ##STR287##                                                                          1             Propyl    Propyl   Propyl                   419                                                                                            ##STR288##                                                                          1             Propyl    Propyl   Butyl                    420                                                                                            ##STR289##                                                                          1             Propyl    Butyl    Butyl                    421                                                                                            ##STR290##                                                                          1             Propyl    H        H                        422                                                                                            ##STR291##                                                                          1             Propyl    H        Methyl                   423                                                                                            ##STR292##                                                                          1             Propyl    H        Ethyl                    424                                                                                            ##STR293##                                                                          1             Propyl    H        Propyl                   425                                                                                            ##STR294##                                                                          1             Propyl    H        Butyl                    426            CF    1             Propyl    Methyl   Methyl                   427                                                                                            ##STR295##                                                                          1             Propyl    Methyl   Ethyl                    428                                                                                            ##STR296##                                                                          1             Propyl    Methyl   Propyl                   429                                                                                            ##STR297##                                                                          1             Propyl    Methyl   Butyl                    430                                                                                            ##STR298##                                                                          1             Propyl    Ethyl    Ethyl                    431                                                                                            ##STR299##                                                                          1             Propyl    Ethyl    Propyl                   432                                                                                            ##STR300##                                                                          1             Propyl    Ethyl    Butyl                    433                                                                                            ##STR301##                                                                          1             Propyl    Propyl   Propyl                   434                                                                                            ##STR302##                                                                          1             Propyl    Propyl   Butyl                    435                                                                                            ##STR303##                                                                          1             Propyl    Butyl    Butyl                    436                                                                                            ##STR304##                                                                          1             Butyl     H        H                        437                                                                                            ##STR305##                                                                          1             Butyl     H        Methyl                   438                                                                                            ##STR306##                                                                          1             Butyl     H        Ethyl                    439                                                                                            ##STR307##                                                                          1             Butyl     H        Propyl                   440                                                                                            ##STR308##                                                                          1             Butyl     H        Butyl                    441                                                                                            ##STR309##                                                                          1             Butyl     Methyl   Methyl                   442                                                                                            ##STR310##                                                                          1             Butyl     Methyl   Ethyl                    443                                                                                            ##STR311##                                                                          1             Butyl     Methyl   Propyl                   444                                                                                            ##STR312##                                                                          1             Butyl     Methyl   Butyl                    445                                                                                            ##STR313##                                                                          1             Butyl     Ethyl    Ethyl                    446                                                                                            ##STR314##                                                                          1             Butyl     Ethyl    Propyl                   447                                                                                            ##STR315##                                                                          1             Butyl     Ethyl    Butyl                    448                                                                                            ##STR316##                                                                          1             Butyl     Propyl   Propyl                   449                                                                                            ##STR317##                                                                          1             Butyl     Propyl   Butyl                    450                                                                                            ##STR318##                                                                          1             Butyl     Butyl    Butyl                    451            CF    1             Butyl     H        H                        452            CF    1             Butyl     H        Methyl                   453            CF    1             Butyl     H        Ethyl                    454                                                                                            ##STR319##                                                                          1             Butyl     H        Propyl                   455                                                                                            ##STR320##                                                                          1             Butyl     H        Butyl                    456                                                                                            ##STR321##                                                                          1             Butyl     Methyl   Methyl                   457                                                                                            ##STR322##                                                                          1             Butyl     Methyl   Ethyl                    458                                                                                            ##STR323##                                                                          1             Butyl     Methyl   Propyl                   459                                                                                            ##STR324##                                                                          1             Butyl     Methyl   Butyl                    460                                                                                            ##STR325##                                                                          1             Butyl     Ethyl    Ethyl                    461                                                                                            ##STR326##                                                                          1             Butyl     Ethyl    Propyl                   462                                                                                            ##STR327##                                                                          1             Butyl     Ethyl    Butyl                    463                                                                                            ##STR328##                                                                          1             Butyl     Propyl   Propyl                   464                                                                                            ##STR329##                                                                          1             Butyl     Propyl   Butyl                    465                                                                                            ##STR330##                                                                          1             Butyl     Butyl    Butyl                    466                                                                                            ##STR331##                                                                          2             Methyl    H        H                        467                                                                                            ##STR332##                                                                          2             Methyl    H        Methyl                   468                                                                                            ##STR333##                                                                          2             Methyl    H        Ethyl                    469                                                                                            ##STR334##                                                                          2             Methyl    H        Propyl                   470                                                                                            ##STR335##                                                                          2             Methyl    H        Butyl                    471                                                                                            ##STR336##                                                                          2             Methyl    Methyl   Methyl                   472                                                                                            ##STR337##                                                                          2             Methyl    Methyl   Ethyl                    473                                                                                            ##STR338##                                                                          2             Methyl    Methyl   Propyl                   474                                                                                            ##STR339##                                                                          2             Methyl    Methyl   Butyl                    475                                                                                            ##STR340##                                                                          2             Methyl    Ethyl    Ethyl                    476                                                                                            ##STR341##                                                                          2             Methyl    Ethyl    Propyl                   477                                                                                            ##STR342##                                                                          2             Methyl    Ethyl    Butyl                    478                                                                                            ##STR343##                                                                          2             Methyl    Propyl   Propyl                   479                                                                                            ##STR344##                                                                          2             Methyl    Propyl   Butyl                    480                                                                                            ##STR345##                                                                          2             Methyl    Butyl    Butyl                    481                                                                                            ##STR346##                                                                          2             Methyl    H        H                        482                                                                                            ##STR347##                                                                          2             Methyl    H        Methyl                   483                                                                                            ##STR348##                                                                          2             Methyl    H        Ethyl                    484                                                                                            ##STR349##                                                                          2             Methyl    H        Propyl                   485                                                                                            ##STR350##                                                                          2             Methyl    H        Butyl                    486                                                                                            ##STR351##                                                                          2             Methyl    Methyl   Methyl                   487                                                                                            ##STR352##                                                                          2             Methyl    Methyl   Ethyl                    488                                                                                            ##STR353##                                                                          2             Methyl    Methyl   Propyl                   489                                                                                            ##STR354##                                                                          2             Methyl    Methyl   Butyl                    490                                                                                            ##STR355##                                                                          2             Methyl    Ethyl    Ethyl                    491                                                                                            ##STR356##                                                                          2             Methyl    Ethyl    Propyl                   492                                                                                            ##STR357##                                                                          2             Methyl    Ethyl    Butyl                    493                                                                                            ##STR358##                                                                          2             Methyl    Propyl   Propyl                   494                                                                                            ##STR359##                                                                          2             Methyl    Propyl   Butyl                    495                                                                                            ##STR360##                                                                          2             Methyl    Butyl    Butyl                    496            CH    2             Ethyl     H        H                        497            CH    2             Ethyl     H        Methyl                   498            CH    2             Ethyl     H        Ethyl                    499                                                                                            ##STR361##                                                                          2             Ethyl     H        Propyl                   500                                                                                            ##STR362##                                                                          2             Ethyl     H        Butyl                    501                                                                                            ##STR363##                                                                          2             Ethyl     Methyl   Methyl                   502                                                                                            ##STR364##                                                                          2             Ethyl     Methyl   Ethyl                    503                                                                                            ##STR365##                                                                          2             Ethyl     Methyl   Propyl                   504                                                                                            ##STR366##                                                                          2             Ethyl     Methyl   Butyl                    505            CH    2             Ethyl     Ethyl    Ethyl                    506            CH    2             Ethyl     Ethyl    Propyl                   507                                                                                            ##STR367##                                                                          2             Ethyl     Ethyl    Butyl                    508                                                                                            ##STR368##                                                                          2             Ethyl     Propyl   Propyl                   509                                                                                            ##STR369##                                                                          2             Ethyl     Propyl   Butyl                    510                                                                                            ##STR370##                                                                          2             Ethyl     Butyl    Butyl                    511                                                                                            ##STR371##                                                                          2             Ethyl     H        H                        512                                                                                            ##STR372##                                                                          2             Ethyl     H        Methyl                   513                                                                                            ##STR373##                                                                          2             Ethyl     H        Ethyl                    514                                                                                            ##STR374##                                                                          2             Ethyl     H        Propyl                   515                                                                                            ##STR375##                                                                          2             Ethyl     H        Butyl                    516                                                                                            ##STR376##                                                                          2             Ethyl     Methyl   Methyl                   517                                                                                            ##STR377##                                                                          2             Ethyl     Methyl   Ethyl                    518                                                                                            ##STR378##                                                                          2             Ethyl     Methyl   Propyl                   519                                                                                            ##STR379##                                                                          2             Ethyl     Methyl   Butyl                    520                                                                                            ##STR380##                                                                          2             Ethyl     Ethyl    Ethyl                    521                                                                                            ##STR381##                                                                          2             Ethyl     Ethyl    Propyl                   522                                                                                            ##STR382##                                                                          2             Ethyl     Ethyl    Butyl                    523                                                                                            ##STR383##                                                                          2             Ethyl     Propyl   Propyl                   524                                                                                            ##STR384##                                                                          2             Ethyl     Propyl   Butyl                    525                                                                                            ##STR385##                                                                          2             Ethyl     Butyl    Butyl                    526                                                                                            ##STR386##                                                                          2             Propyl    H        H                        527                                                                                            ##STR387##                                                                          2             Propyl    H        Methyl                   528                                                                                            ##STR388##                                                                          2             Propyl    H        Ethyl                    529                                                                                            ##STR389##                                                                          2             Propyl    H        Propyl                   530                                                                                            ##STR390##                                                                          2             Propyl    H        Butyl                    531                                                                                            ##STR391##                                                                          2             Propyl    Methyl   Methyl                   532                                                                                            ##STR392##                                                                          2             Propyl    Methyl   Ethyl                    533                                                                                            ##STR393##                                                                          2             Propyl    Methyl   Propyl                   534                                                                                            ##STR394##                                                                          2             Propyl    Methyl   Butyl                    535                                                                                            ##STR395##                                                                          2             Propyl    Ethyl    Ethyl                    536                                                                                            ##STR396##                                                                          2             Propyl    Ethyl    Propyl                   537                                                                                            ##STR397##                                                                          2             Propyl    Ethyl    Butyl                    538                                                                                            ##STR398##                                                                          2             Propyl    Propyl   Propyl                   539                                                                                            ##STR399##                                                                          2             Propyl    Propyl   Butyl                    540                                                                                            ##STR400##                                                                          2             Propyl    Butyl    Butyl                    541            CF    2             Propyl    H        H                        542            CF    2             Propyl    H        Methyl                   543            CF    2             Propyl    H        Ethyl                    544            CF    2             Propyl    H        Propyl                   545                                                                                            ##STR401##                                                                          2             Propyl    H        Butyl                    546                                                                                            ##STR402##                                                                          2             Propyl    Methyl   Methyl                   547                                                                                            ##STR403##                                                                          2             Propyl    Methyl   Ethyl                    548                                                                                            ##STR404##                                                                          2             Propyl    Methyl   Propyl                   549                                                                                            ##STR405##                                                                          2             Propyl    Methyl   Butyl                    550                                                                                            ##STR406##                                                                          2             Propyl    Ethyl    Ethyl                    551                                                                                            ##STR407##                                                                          2             Propyl    Ethyl    Propyl                   552                                                                                            ##STR408##                                                                          2             Propyl    Ethyl    Butyl                    553                                                                                            ##STR409##                                                                          2             Propyl    Propyl   Propyl                   554                                                                                            ##STR410##                                                                          2             Propyl    Propyl   Butyl                    555                                                                                            ##STR411##                                                                          2             Propyl    Butyl    Butyl                    556                                                                                            ##STR412##                                                                          2             Butyl     H        H                        557                                                                                            ##STR413##                                                                          2             Butyl     H        Methyl                   558                                                                                            ##STR414##                                                                          2             Butyl     H        Ethyl                    559                                                                                            ##STR415##                                                                          2             Butyl     H        Propyl                   560                                                                                            ##STR416##                                                                          2             Butyl     H        Butyl                    561                                                                                            ##STR417##                                                                          2             Butyl     Methyl   Methyl                   562                                                                                            ##STR418##                                                                          2             Butyl     Methyl   Ethyl                    563                                                                                            ##STR419##                                                                          2             Butyl     Methyl   Propyl                   564                                                                                            ##STR420##                                                                          2             Butyl     Methyl   Butyl                    565                                                                                            ##STR421##                                                                          2             Butyl     Ethyl    Ethyl                    566                                                                                            ##STR422##                                                                          2             Butyl     Ethyl    Propyl                   567                                                                                            ##STR423##                                                                          2             Butyl     Ethyl    Butyl                    568                                                                                            ##STR424##                                                                          2             Butyl     Propyl   Propyl                   569                                                                                            ##STR425##                                                                          2             Butyl     Propyl   Butyl                    570                                                                                            ##STR426##                                                                          2             Butyl     Butyl    Butyl                    571                                                                                            ##STR427##                                                                          2             Butyl     H        H                        572                                                                                            ##STR428##                                                                          2             Butyl     H        Methyl                   573                                                                                            ##STR429##                                                                          2             Butyl     H        Ethyl                    574                                                                                            ##STR430##                                                                          2             Butyl     H        Propyl                   575                                                                                            ##STR431##                                                                          2             Butyl     H        Butyl                    576                                                                                            ##STR432##                                                                          2             Butyl     Methyl   Methyl                   577                                                                                            ##STR433##                                                                          2             Butyl     Methyl   Ethyl                    578                                                                                            ##STR434##                                                                          2             Butyl     Methyl   Propyl                   579                                                                                            ##STR435##                                                                          2             Butyl     Methyl   Butyl                    580                                                                                            ##STR436##                                                                          2             Butyl     Ethyl    Ethyl                    581            CF    2             Butyl     Ethyl    Propyl                   582            CF    2             Butyl     Ethyl    Butyl                    583                                                                                            ##STR437##                                                                          2             Butyl     Propyl   Propyl                   584                                                                                            ##STR438##                                                                          2             Butyl     Propyl   Butyl                    585                                                                                            ##STR439##                                                                          2             Butyl     Butyl    Butyl                    586            CH    3             Methyl    H        H                        587                                                                                            ##STR440##                                                                          3             Methyl    H        Methyl                   588                                                                                            ##STR441##                                                                          3             Methyl    H        Ethyl                    589                                                                                            ##STR442##                                                                          3             Methyl    H        Propyl                   590                                                                                            ##STR443##                                                                          3             Methyl    H        Butyl                    591                                                                                            ##STR444##                                                                          3             Methyl    Methyl   Methyl                   592                                                                                            ##STR445##                                                                          3             Methyl    Methyl   Ethyl                    593                                                                                            ##STR446##                                                                          3             Methyl    Methyl   Propyl                   594                                                                                            ##STR447##                                                                          3             Methyl    Methyl   Butyl                    595                                                                                            ##STR448##                                                                          3             Methyl    Ethyl    Ethyl                    596                                                                                            ##STR449##                                                                          3             Methyl    Ethyl    Propyl                   597                                                                                            ##STR450##                                                                          3             Methyl    Ethyl    Butyl                    598                                                                                            ##STR451##                                                                          3             Methyl    Propyl   Propyl                   599                                                                                            ##STR452##                                                                          3             Methyl    Propyl   Butyl                    600                                                                                            ##STR453##                                                                          3             Methyl    Butyl    Butyl                    601                                                                                            ##STR454##                                                                          3             Methyl    H        H                        602                                                                                            ##STR455##                                                                          3             Methyl    H        Methyl                   603                                                                                            ##STR456##                                                                          3             Methyl    H        Ethyl                    604            CF    3             Methyl    H        Propyl                   605            CF    3             Methyl    H        Butyl                    606            CF    3             Methyl    Methyl   Methyl                   607                                                                                            ##STR457##                                                                          3             Methyl    Methyl   Ethyl                    608            CF    3             Methyl    Methyl   Propyl                   609                                                                                            ##STR458##                                                                          3             Methyl    Methyl   Butyl                    610                                                                                            ##STR459##                                                                          3             Methyl    Ethyl    Ethyl                    611                                                                                            ##STR460##                                                                          3             Methyl    Ethyl    Propyl                   612                                                                                            ##STR461##                                                                          3             Methyl    Ethyl    Butyl                    613                                                                                            ##STR462##                                                                          3             Methyl    Propyl   Propyl                   614                                                                                            ##STR463##                                                                          3             Methyl    Propyl   Butyl                    615                                                                                            ##STR464##                                                                          3             Methyl    Butyl    Butyl                    616                                                                                            ##STR465##                                                                          3             Ethyl     H        H                        617                                                                                            ##STR466##                                                                          3             Ethyl     H        Methyl                   618                                                                                            ##STR467##                                                                          3             Ethyl     H        Ethyl                    619                                                                                            ##STR468##                                                                          3             Ethyl     H        Propyl                   620                                                                                            ##STR469##                                                                          3             Ethyl     H        Butyl                    621                                                                                            ##STR470##                                                                          3             Ethyl     Methyl   Methyl                   622            CH    3             Ethyl     Methyl   Ethyl                    623            CH    3             Ethyl     Methyl   Propyl                   624                                                                                            ##STR471##                                                                          3             Ethyl     Methyl   Butyl                    625                                                                                            ##STR472##                                                                          3             Ethyl     Ethyl    Ethyl                    626                                                                                            ##STR473##                                                                          3             Ethyl     Ethyl    Propyl                   627                                                                                            ##STR474##                                                                          3             Ethyl     Ethyl    Butyl                    628                                                                                            ##STR475##                                                                          3             Ethyl     Propyl   Propyl                   629                                                                                            ##STR476##                                                                          3             Ethyl     Propyl   Butyl                    630                                                                                            ##STR477##                                                                          3             Ethyl     Butyl    Butyl                    631            C F   3             Ethyl     H        H                        632            CF    3             Ethyl     H        Methyl                   633                                                                                            ##STR478##                                                                          3             Ethyl     H        Ethyl                    634                                                                                            ##STR479##                                                                          3             Ethyl     H        Propyl                   635                                                                                            ##STR480##                                                                          3             Ethyl     H        Butyl                    636                                                                                            ##STR481##                                                                          3             Ethyl     Methyl   Methyl                   637                                                                                            ##STR482##                                                                          3             Ethyl     Methyl   Ethyl                    638                                                                                            ##STR483##                                                                          3             Ethyl     Methyl   Propyl                   639                                                                                            ##STR484##                                                                          3             Ethyl     Methyl   Butyl                    640                                                                                            ##STR485##                                                                          3             Ethyl     Ethyl    Ethyl                    641                                                                                            ##STR486##                                                                          3             Ethyl     Ethyl    Propyl                   642                                                                                            ##STR487##                                                                          3             Ethyl     Ethyl    Butyl                    643                                                                                            ##STR488##                                                                          3             Ethyl     Propyl   Propyl                   644                                                                                            ##STR489##                                                                          3             Ethyl     Propyl   Butyl                    645                                                                                            ##STR490##                                                                          3             Ethyl     Butyl    Butyl                    646                                                                                            ##STR491##                                                                          3             Propyl    H        H                        647                                                                                            ##STR492##                                                                          3             Propyl    H        Methyl                   648                                                                                            ##STR493##                                                                          3             Propyl    H        Ethyl                    649                                                                                            ##STR494##                                                                          3             Propyl    H        Propyl                   650                                                                                            ##STR495##                                                                          3             Propyl    H        Butyl                    651                                                                                            ##STR496##                                                                          3             Propyl    Methyl   Methyl                   652                                                                                            ##STR497##                                                                          3             Propyl    Methyl   Ethyl                    653                                                                                            ##STR498##                                                                          3             Propyl    Methyl   Propyl                   654                                                                                            ##STR499##                                                                          3             Propyl    Methyl   Butyl                    655                                                                                            ##STR500##                                                                          3             Propyl    Ethyl    Ethyl                    656                                                                                            ##STR501##                                                                          3             Propyl    Ethyl    Propyl                   657                                                                                            ##STR502##                                                                          3             Propyl    Ethyl    Butyl                    658                                                                                            ##STR503##                                                                          3             Propyl    Propyl   Propyl                   659                                                                                            ##STR504##                                                                          3             Propyl    Propyl   Butyl                    660                                                                                            ##STR505##                                                                          3             Propyl    Butyl    Butyl                    661                                                                                            ##STR506##                                                                          3             Propyl    H        H                        662                                                                                            ##STR507##                                                                          3             Propyl    H        Methyl                   663                                                                                            ##STR508##                                                                          3             Propyl    H        Ethyl                    664                                                                                            ##STR509##                                                                          3             Propyl    H        Propyl                   665                                                                                            ##STR510##                                                                          3             Propyl    H        Butyl                    666                                                                                            ##STR511##                                                                          3             Propyl    Methyl   Methyl                   667                                                                                            ##STR512##                                                                          3             Propyl    Methyl   Ethyl                    668                                                                                            ##STR513##                                                                          3             Propyl    Methyl   Propyl                   669                                                                                            ##STR514##                                                                          3             Propyl    Methyl   Butyl                    670                                                                                            ##STR515##                                                                          3             Propyl    Ethyl    Ethyl                    671                                                                                            ##STR516##                                                                          3             Propyl    Ethyl    Propyl                   672                                                                                            ##STR517##                                                                          3             Propyl    Ethyl    Butyl                    673                                                                                            ##STR518##                                                                          3             Propyl    Propyl   Propyl                   674                                                                                            ##STR519##                                                                          3             Propyl    Propyl   Butyl                    675                                                                                            ##STR520##                                                                          3             Propyl    Butyl    Butyl                    676            CH    3             Butyl     H        H                        677            CH    3             Butyl     H        Methyl                   678            CH    3             Butyl     H        Ethyl                    679                                                                                            ##STR521##                                                                          3             Butyl     H        Propyl                   680                                                                                            ##STR522##                                                                          3             Butyl     H        Butyl                    681                                                                                            ##STR523##                                                                          3             Butyl     Methyl   Methyl                   682                                                                                            ##STR524##                                                                          3             Butyl     Methyl   Ethyl                    683                                                                                            ##STR525##                                                                          3             Butyl     Methyl   Propyl                   684                                                                                            ##STR526##                                                                          3             Butyl     Methyl   Butyl                    685            CH    3             Butyl     Ethyl    Ethyl                    686                                                                                            ##STR527##                                                                          3             Butyl     Ethyl    Propyl                   687                                                                                            ##STR528##                                                                          3             Butyl     Ethyl    Butyl                    688                                                                                            ##STR529##                                                                          3             Butyl     Propyl   Propyl                   689                                                                                            ##STR530##                                                                          3             Butyl     Propyl   Butyl                    690                                                                                            ##STR531##                                                                          3             Butyl     Butyl    Butyl                    691                                                                                            ##STR532##                                                                          3             Propyl    H        H                        692                                                                                            ##STR533##                                                                          3             Butyl     H        Methyl                   693                                                                                            ##STR534##                                                                          3             Butyl     H        Ethyl                    694                                                                                            ##STR535##                                                                          3             Butyl     H        Propyl                   695                                                                                            ##STR536##                                                                          3             Butyl     H        Butyl                    696                                                                                            ##STR537##                                                                          3             Butyl     Methyl   Methyl                   697                                                                                            ##STR538##                                                                          3             Butyl     Methyl   Ethyl                    698                                                                                            ##STR539##                                                                          3             Butyl     Methyl   Propyl                   699                                                                                            ##STR540##                                                                          3             Butyl     Methyl   Butyl                    700                                                                                            ##STR541##                                                                          3             Butyl     Ethyl    Ethyl                    701                                                                                            ##STR542##                                                                          3             Butyl     Ethyl    Propyl                   702                                                                                            ##STR543##                                                                          3             Butyl     Ethyl    Butyl                    703                                                                                            ##STR544##                                                                          3             Butyl     Propyl   Propyl                   704                                                                                            ##STR545##                                                                          3             Butyl     Propyl   Butyl                    705                                                                                            ##STR546##                                                                          3             Butyl     Butyl    Butyl                    706            CH    4             Methyl    H        H                        707            CH    4             Methyl    H        Methyl                   708            CH    4             Methyl    H        Ethyl                    709                                                                                            ##STR547##                                                                          4             Methyl    H        Propyl                   710                                                                                            ##STR548##                                                                          4             Methyl    H        Butyl                    711                                                                                            ##STR549##                                                                          4             Methyl    Methyl   Methyl                   712                                                                                            ##STR550##                                                                          4             Methyl    Methyl   Ethyl                    713                                                                                            ##STR551##                                                                          4             Methyl    Methyl   Propyl                   714                                                                                            ##STR552##                                                                          4             Methyl    Methyl   Butyl                    715            CH    4             Methyl    Ethyl    Ethyl                    716            CH    4             Methyl    Ethyl    Propyl                   717                                                                                            ##STR553##                                                                          4             Methyl    Ethyl    Butyl                    718                                                                                            ##STR554##                                                                          4             Methyl    Propyl   Propyl                   719                                                                                            ##STR555##                                                                          4             Methyl    Propyl   Butyl                    720                                                                                            ##STR556##                                                                          4             Methyl    Butyl    Butyl                    721            CF    4             Methyl    H        H                        722            CF    4             Methyl    H        Methyl                   723            CF    4             Methyl    H        Ethyl                    724            CF    4             Methyl    H        Propyl                   725            CF    4             Methyl    H        Butyl                    726            CF    4             Methyl    Methyl   Methyl                   727                                                                                            ##STR557##                                                                          4             Methyl    Methyl   Ethyl                    728                                                                                            ##STR558##                                                                          4             Methyl    Methyl   Propyl                   729                                                                                            ##STR559##                                                                          4             Methyl    Methyl   Butyl                    730            CF    4             Methyl    Ethyl    Ethyl                    731                                                                                            ##STR560##                                                                          4             Methyl    Ethyl    Propyl                   732                                                                                            ##STR561##                                                                          4             Methyl    Ethyl    Butyl                    733                                                                                            ##STR562##                                                                          4             Methyl    Propyl   Propyl                   734                                                                                            ##STR563##                                                                          4             Methyl    Propyl   Butyl                    735                                                                                            ##STR564##                                                                          4             Methyl    Butyl    Butyl                    736                                                                                            ##STR565##                                                                          4             Ethyl     H        H                        737                                                                                            ##STR566##                                                                          4             Ethyl     H        Methyl                   738                                                                                            ##STR567##                                                                          4             Ethyl     H        Ethyl                    739                                                                                            ##STR568##                                                                          4             Ethyl     H        Propyl                   740                                                                                            ##STR569##                                                                          4             Ethyl     H        Butyl                    741                                                                                            ##STR570##                                                                          4             Ethyl     Methyl   Methyl                   742                                                                                            ##STR571##                                                                          4             Ethyl     Methyl   Ethyl                    743                                                                                            ##STR572##                                                                          4             Ethyl     Methyl   Propyl                   744                                                                                            ##STR573##                                                                          4             Ethyl     Methyl   Butyl                    745                                                                                            ##STR574##                                                                          4             Ethyl     Ethyl    Ethyl                    746                                                                                            ##STR575##                                                                          4             Ethyl     Ethyl    Propyl                   747                                                                                            ##STR576##                                                                          4             Ethyl     Ethyl    Butyl                    748                                                                                            ##STR577##                                                                          4             Ethyl     Propyl   Propyl                   749                                                                                            ##STR578##                                                                          4             Ethyl     Propyl   Butyl                    750                                                                                            ##STR579##                                                                          4             Ethyl     Butyl    Butyl                    751                                                                                            ##STR580##                                                                          4             Ethyl     H        H                        752                                                                                            ##STR581##                                                                          4             Ethyl     H        Methyl                   753                                                                                            ##STR582##                                                                          4             Ethyl     H        Ethyl                    754                                                                                            ##STR583##                                                                          4             Ethyl     H        Propyl                   755                                                                                            ##STR584##                                                                          4             Ethyl     H        Butyl                    756            CF    4             Ethyl     Methyl   Methyl                   757            CF    4             Ethyl     Methyl   Ethyl                    758            CF    4             Ethyl     Methyl   Propyl                   759            CF    4             Ethyl     Methyl   Butyl                    760            CF    4             Ethyl     Ethyl    Ethyl                    761                                                                                            ##STR585##                                                                          4             Ethyl     Ethyl    Propyl                   762            CF    4             Ethyl     Ethyl    Butyl                    763                                                                                            ##STR586##                                                                          4             Ethyl     Propyl   Propyl                   764                                                                                            ##STR587##                                                                          4             Ethyl     Propyl   Butyl                    765                                                                                            ##STR588##                                                                          4             Ethyl     Butyl    Butyl                    766            CH    4             Propyl    H        H                        767            CH    4             Propyl    H        Methyl                   768                                                                                            ##STR589##                                                                          4             Propyl    H        Ethyl                    769                                                                                            ##STR590##                                                                          4             Propyl    H        Propyl                   770                                                                                            ##STR591##                                                                          4             Propyl    H        Butyl                    771                                                                                            ##STR592##                                                                          4             Propyl    Methyl   Methyl                   772                                                                                            ##STR593##                                                                          4             Propyl    Methyl   Ethyl                    773                                                                                            ##STR594##                                                                          4             Propyl    Methyl   Propyl                   774                                                                                            ##STR595##                                                                          4             Propyl    Methyl   Butyl                    775                                                                                            ##STR596##                                                                          4             Propyl    Ethyl    Ethyl                    776                                                                                            ##STR597##                                                                          4             Propyl    Ethyl    Propyl                   777                                                                                            ##STR598##                                                                          4             Propyl    Ethyl    Butyl                    778                                                                                            ##STR599##                                                                          4             Propyl    Propyl   Propyl                   779                                                                                            ##STR600##                                                                          4             Propyl    Propyl   Butyl                    780                                                                                            ##STR601##                                                                          4             Propyl    Butyl    Butyl                    781                                                                                            ##STR602##                                                                          4             Propyl    H        H                        782                                                                                            ##STR603##                                                                          4             Propyl    H        Methyl                   783                                                                                            ##STR604##                                                                          4             Propyl    H        Ethyl                    784                                                                                            ##STR605##                                                                          4             Propyl    H        Propyl                   785                                                                                            ##STR606##                                                                          4             Propyl    H        Butyl                    786                                                                                            ##STR607##                                                                          4             Propyl    Methyl   Methyl                   787                                                                                            ##STR608##                                                                          4             Propyl    Methyl   Ethyl                    788                                                                                            ##STR609##                                                                          4             Propyl    Methyl   Propyl                   789                                                                                            ##STR610##                                                                          4             Propyl    Methyl   Butyl                    790                                                                                            ##STR611##                                                                          4             Propyl    Ethyl    Ethyl                    791                                                                                            ##STR612##                                                                          4             Propyl    Ethyl    Propyl                   792                                                                                            ##STR613##                                                                          4             Propyl    Ethyl    Butyl                    793                                                                                            ##STR614##                                                                          4             Propyl    Propyl   Propyl                   794                                                                                            ##STR615##                                                                          4             Propyl    Propyl   Butyl                    795                                                                                            ##STR616##                                                                          4             Propyl    Butyl    Butyl                    796                                                                                            ##STR617##                                                                          4             Butyl     H        H                        797            CH    4             Butyl     H        Methyl                   798                                                                                            ##STR618##                                                                          4             Butyl     H        Ethyl                    799                                                                                            ##STR619##                                                                          4             Butyl     H        Propyl                   800                                                                                            ##STR620##                                                                          4             Butyl     H        Butyl                    801                                                                                            ##STR621##                                                                          4             Butyl     Methyl   Methyl                   802                                                                                            ##STR622##                                                                          4             Butyl     Methyl   Ethyl                    803                                                                                            ##STR623##                                                                          4             Butyl     Methyl   Propyl                   804                                                                                            ##STR624##                                                                          4             Butyl     Methyl   Butyl                    805                                                                                            ##STR625##                                                                          4             Butyl     Ethyl    Ethyl                    806                                                                                            ##STR626##                                                                          4             Butyl     Ethyl    Propyl                   807                                                                                            ##STR627##                                                                          4             Butyl     Ethyl    Butyl                    808                                                                                            ##STR628##                                                                          4             Butyl     Propyl   Propyl                   809                                                                                            ##STR629##                                                                          4             Butyl     Propyl   Butyl                    810                                                                                            ##STR630##                                                                          4             Butyl     Butyl    Butyl                    811                                                                                            ##STR631##                                                                          4             Butyl     H        H                        812                                                                                            ##STR632##                                                                          4             Butyl     H        Methyl                   813                                                                                            ##STR633##                                                                          4             Butyl     H        Ethyl                    814                                                                                            ##STR634##                                                                          4             Butyl     H        Propyl                   815                                                                                            ##STR635##                                                                          4             Butyl     H        Butyl                    816                                                                                            ##STR636##                                                                          4             Butyl     Methyl   Methyl                   817                                                                                            ##STR637##                                                                          4             Butyl     Methyl   Ethyl                    818                                                                                            ##STR638##                                                                          4             Butyl     Methyl   Propyl                   819            CF    4             Butyl     Methyl   Butyl                    820                                                                                            ##STR639##                                                                          4             Butyl     Ethyl    Ethyl                    821                                                                                            ##STR640##                                                                          4             Butyl     Ethyl    Propyl                   822                                                                                            ##STR641##                                                                          4             Butyl     Ethyl    Butyl                    823                                                                                            ##STR642##                                                                          4             Butyl     Propyl   Propyl                   824                                                                                            ##STR643##                                                                          4             Butyl     Propyl   Butyl                    825                                                                                            ##STR644##                                                                          4             Butyl     Butyl    Butyl                    826            NO    0             Methyl    H        H                        827            NO    0             Methyl    H        Methyl                   828            NO    0             Methyl    H        Ethyl                    829             NO   0             Methyl    H        Propyl                   830            NO    0             Methyl    H        Butyl                    831            NO    0             Methyl    Methyl   Methyl                   832            NO    0             Methyl    Methyl   Ethyl                    833            NO    0             Methyl    Methyl   Propyl                   834            NO    0             Methyl    Methyl   Butyl                    835            NO    0             Methyl    Ethyl    Ethyl                    836            NO    0             Methyl    Ethyl    Propyl                   837            NO    0             Methyl    Ethyl    Butyl                    838            NO    0             Methyl    Propyl   Propyl                   839            NO    0             Methyl    Propyl   Butyl                    840            NO    0             Methyl    Butyl    Butyl                    841            NO    1             Methyl    H        H                        842            NO    1             Methyl    H        Methyl                   843            NO    1             Methyl    H        Ethyl                    844            NO    1             Methyl    H        Propyl                   845            NO    1             Methyl    H        Butyl                    846            NO    1             Methyl    Methyl   Methyl                   847            NO    1             Methyl    Methyl   Ethyl                    848            NO    1             Methyl    Methyl   Propyl                   849            NO    1             Methyl    Methyl   Butyl                    850            NO    1             Methyl    Ethyl    Ethyl                    851            NO    1             Methyl    Ethyl    Propyl                   852            NO    1             Methyl    Ethyl    Butyl                    853            NO    1             Methyl    Propyl   Propyl                   854            NO    1             Methyl    Propyl   Butyl                    855            NO    1             Methyl    Butyl    Butyl                    856            NO    2             Ethyl     H        H                        857            NO    2             Ethyl     H        Methyl                   858            NO    2             Ethyl     H        Ethyl                    859            NO    2             Ethyl     H        Propyl                   860            NO    2             Ethyl     H        Butyl                    861            NO    2             Ethyl     Methyl   Methyl                   862            NO    2             Ethyl     Methyl   Ethyl                    863            NO    2             Ethyl     Methyl   Propyl                   864            NO    2             Ethyl     Methyl   Butyl                    865            NO    2             Ethyl     Ethyl    Ethyl                    866            NO    2             Ethyl     Ethyl    Propyl                   867            NO    2             Ethyl     Ethyl    Butyl                    868            NO    2             Ethyl     Propyl   Propyl                   869            NO    2             Ethyl     Propyl   Butyl                    870            NO    2             Ethyl     Butyl    Butyl                    871            NO    3             Ethyl     H        H                        872            NO    3             Ethyl     H        Methyl                   873            NO    3             Ethyl     H        Ethyl                    874            NO    3             Ethyl     H        Propyl                   875            NO    3             Ethyl     H        Butyl                    876            NO    3             Ethyl     Methyl   Methyl                   877            NO    3             Ethyl     Methyl   Ethyl                    878            NO    3             Ethyl     Methyl   Propyl                   879            NO    3             Ethyl     Methyl   Butyl                    880            NO    3             Ethyl     Ethyl    Ethyl                    881            NO    3             Ethyl     Ethyl    Propyl                   882            NO    3             Ethyl     Ethyl    Butyl                    883            NO    3             Ethyl     Propyl   Propyl                   884            NO    3             Ethyl     Propyl   Butyl                    885            NO    3             Ethyl     Butyl    Butyl                    886            NO    4             Propyl    H        H                        887            NO    4             Propyl    H        Methyl                   888            NO    4             Propyl    H        Ethyl                    889            NO    4             Propyl    H        Propyl                   890            NO    4             Propyl    H        Butyl                    891            NO    4             Propyl    Methyl   Methyl                   892            NO    4             Propyl    Methyl   Ethyl                    893            NO    4             Propyl    Methyl   Propyl                   894            NO    4             Propyl    Methyl   Butyl                    895            NO    4             Propyl    Ethyl    Ethyl                    896            NO    4             Propyl    Ethyl    Propyl                   897            NO    4             Propyl    Ethyl    Butyl                    898            NO    4             Propyl    Propyl   Propyl                   899            NO    4             Propyl    Propyl   Butyl                    900            NO    4             Propyl    Butyl    Butyl                    901            NO    0             Propyl    H        H                        902            NO    0             Propyl    H        Methyl                   903            NO    0             Propyl    H        Ethyl                    904            NO    0             Propyl    H        Propyl                   905            NO    0             Propyl    H        Butyl                    906            NO    0             Propyl    Methyl   Methyl                   907            NO    0             Propyl    Methyl   Ethyl                    908            NO    0             Propyl    Methyl   Propyl                   909            NO    0             Propyl    Methyl   Butyl                    910            NO    0             Propyl    Ethyl    Ethyl                    911            NO    0             Propyl    Ethyl    Propyl                   912            NO    0             Propyl    Ethyl    Butyl                    913            NO    0             Propyl    Propyl   Propyl                   914            NO    0             Propyl    Propyl   Butyl                    915            NO    0             Propyl    Butyl    Butyl                    916            NO    0             Butyl     H        H                        917            NO    0             Butyl     H        Methyl                   918            NO    0             Butyl     H        Ethyl                    919            NO    0             Butyl     H        Propyl                   920            NO    0             Butyl     H        Butyl                    921            NO    0             Butyl     Methyl   Methyl                   922            NO    0             Butyl     Methyl   Ethyl                    923            NO    0             Butyl     Methyl   Propyl                   924            NO    0             Butyl     Methyl   Butyl                    925            NO    0             Butyl     Ethyl    Ethyl                    926            NO    0             Butyl     Ethyl    Propyl                   927            NO    0             Butyl     Ethyl    Butyl                    928            NO    0             Butyl     Propyl   Propyl                   929            NO    0             Butyl     Propyl   Butyl                    930            NO    0             Butyl     Butyl    Butyl                    931            NO    0             Butyl     H        H                        932            NO    1             Butyl     H        Methyl                   933            NO    1             Butyl     H        Ethyl                    934            NO    1             Butyl     H        Propyl                   935            NO    1             Butyl     H        Butyl                    936            NO    1             Butyl     Methyl   Methyl                   937            NO    1             Butyl     Methyl   Ethyl                    938            NO    1             Butyl     Methyl   Propyl                   939            NO    1             Butyl     Methyl   Butyl                    940            N O   1             Butyl     Ethyl    Ethyl                    941            NO    1             Butyl     Ethyl    Propyl                   942            NO    1             Butyl     Ethyl    Butyl                    943            NO    1             Butyl     Propyl   Propyl                   944            NO    1             Butyl     Propyl   Butyl                    945            NO    1             Butyl     Butyl    Butyl                    946            NO    2             Methyl    H        H                        947            NO    2             Methyl    H        Methyl                   948            NO    2             Methyl    H        Ethyl                    949            NO    2             Methyl    H        Propyl                   950            NO    2             Methyl    H        Butyl                    951            NO    2             Methyl    Methyl   Methyl                   952            NO    2             Methyl    Methyl   Ethyl                    953            NO    2             Methyl    Methyl   Propyl                   954            NO    2             Methyl    Methyl   Butyl                    955            NO    2             Methyl    Ethyl    Ethyl                    956            NO    2             Methyl    Ethyl    Propyl                   957            NO    2             Methyl    Ethyl    Butyl                    958            NO    2             Methyl    Propyl   Propyl                   959            NO    2             Methyl    Propyl   Butyl                    960            NO    2             Methyl    Butyl    Butyl                    961            NO    3             Methyl    H        H                        962            NO    3             Methyl    H        Methyl                   963            NO    3             Methyl    H        Ethyl                    964            NO    3             Methyl    H        Propyl                   965            NO    3             Methyl    H        Butyl                    966            NO    3             Methyl    Methyl   Methyl                   967            NO    3             Methyl    Methyl   Ethyl                    968            NO    3             Methyl    Methyl   Propyl                   969            NO    3             Methyl    Methyl   Butyl                    970            NO    3             Methyl    Ethyl    Ethyl                    971            NO    3             Methyl    Ethyl    Propyl                   972            NO    3             Methyl    Ethyl    Butyl                    973            NO    3             Methyl    Propyl   Propyl                   974            NO    3             Methyl    Propyl   Butyl                    975            NO    3             Methyl    Butyl    Butyl                    976            NO    4             Ethyl     H        H                        977            NO    4             Ethyl     H        Methyl                   978            NO    4             Ethyl     H        Ethyl                    979            NO    4             Ethyl     H        Propyl                   980            NO    4             Ethyl     H        Butyl                    981            NO    4             Ethyl     Methyl   Methyl                   982            NO    4             Ethyl     Methyl   Ethyl                    983            NO    4             Ethyl     Methyl   Propyl                   984            NO    4             Ethyl     Methyl   Butyl                    985            NO    4             Ethyl     Ethyl    Ethyl                    986            NO    4             Ethyl     Ethyl    Propyl                   987            NO    4             Ethyl     Ethyl    Butyl                    988            NO    4             Ethyl     Propyl   Propyl                   989            NO    4             Ethyl     Propyl   Butyl                    990            NO    4             Ethyl     Butyl    Butyl                    991            NO    0             Ethyl     H        H                        992            NO    0             Ethyl     H        Methyl                   993            NO    0             Ethyl     H        Ethyl                    994            NO    0             Ethyl     H        Propyl                   995            NO    0             Ethyl     H        Butyl                    996            NO    0             Ethyl     Methyl   Methyl                   997            NO    0             Ethyl     Methyl   Ethyl                    998            NO    0             Ethyl     Methyl   Propyl                   999            NO    0             Ethyl     Methyl   Butyl                    1000           NO    0             Ethyl     Ethyl    Ethyl                    1001           NO    0             Ethyl     Ethyl    Propyl                   1002           NO    0             Ethyl     Ethyl    Butyl                    1003           NO    0             Ethyl     Propyl   Propyl                   1004           NO    0             Ethyl     Propyl   Butyl                    1005           NO    0             Ethyl     Butyl    Butyl                    1006           NO    1             Propyl    H        H                        1007           NO    1             Propyl    H        Methyl                   1008           NO    1             Propyl    H        Ethyl                    1009           NO    1             Propyl    H        Propyl                   1010           NO    1             Propyl    H        Butyl                    1011           NO    1             Propyl    Methyl   Methyl                   1012           NO    1             Propyl    Methyl   Ethyl                    1013           NO    1             Propyl    Methyl   Propyl                   1014           NO    1             Propyl    Methyl   Butyl                    1015           NO    1             Propyl    Ethyl    Ethyl                    1016           NO    1             Propyl    Ethyl    Propyl                   1017           NO    1             Propyl    Ethyl    Butyl                    1018           NO    1             Propyl    Propyl   Propyl                   1019           NO    1             Propyl    Propyl   Butyl                    1020           NO    1             Propyl    Butyl    Butyl                    1021           NO    2             Propyl    H        H                        1022           NO    2             Propyl    H        Methyl                   1023           NO    2             Propyl    H        Ethyl                    1024           NO    2             Propyl    H        Propyl                   1025           NO    2             Propyl    H        Butyl                    1026           NO    2             Propyl    Methyl   Methyl                   1027           NO    2             Propyl    Methyl   Ethyl                    1028           NO    2             Propyl    Methyl   Propyl                   1029            NO   2             Propyl    Methyl   Butyl                    1030           NO    2             Propyl    Ethyl    Ethyl                    1031           NO    2             Propyl    Ethyl    Propyl                   1032           NO    2             Propyl    Ethyl    Butyl                    1033           NO    2             Propyl    Propyl   Propyl                   1034           NO    2             Propyl    Propyl   Butyl                    1035           NO    2             Propyl    Butyl    Butyl                    1036           NO    3             Butyl     H        H                        1037           NO    3             Butyl     H        Methyl                   1038           NO    3             Butyl     H        Ethyl                    1039           NO    3             Butyl     H        Propyl                   1040           NO    3             Butyl     H        Butyl                    1041           NO    3             Butyl     Methyl   Methyl                   1042           NO    3             Butyl     Methyl   Ethyl                    1043           NO    3             Butyl     Methyl   Propyl                   1044           NO    3             Butyl     Methyl   Butyl                    1045           NO    3             Butyl     Ethyl    Ethyl                    1046           NO    3             Butyl     Ethyl    Propyl                   1047           NO    3             Butyl     Ethyl    Butyl                    1048           NO    3             Butyl     Propyl   Propyl                   1049           NO    3             Butyl     Propyl   Butyl                    1050           NO    3             Butyl     Butyl    Butyl                    1051           NO    4             Butyl     H        H                        1052           NO    4             Butyl     H        Methyl                   1053           NO    4             Butyl     H        Ethyl                    1054           NO    4             Butyl     H        Propyl                   1055           NO    4             Butyl     H        Butyl                    1056           NO    4             Butyl     Methyl   Methyl                   1057           NO    4             Butyl     Methyl   Ethyl                    1058           NO    4             Butyl     Methyl   Propyl                   1059           NO    4             Butyl     Methyl   Butyl                    1060           NO    4             Butyl     Ethyl    Ethyl                    1061           NO    4             Butyl     Ethyl    Propyl                   1062           NO    4             Butyl     Ethyl    Butyl                    1063           NO    4             Butyl     Propyl   Propyl                   1064           NO    4             Butyl     Propyl   Butyl                    1065           NO    4             Butyl     Butyl    Butyl                    1066           NO    4             Methyl    H        H                        1067           NO    4             Methyl    H        Methyl                   1068           NO    4             Methyl    H        Ethyl                    1069           NO    4             Methyl    H        Propyl                   1070           NO    4             Methyl    H        Butyl                    1071           NO    4             Methyl    Methyl   Methyl                   1072           NO    4             Methyl    Methyl   Ethyl                    1073           NO    4             Methyl    Methyl   Propyl                   1074           NO    4             Methyl    Methyl   Butyl                    1075           NO    4             Methyl    Ethyl    Ethyl                    1076           NO    4             Methyl    Ethyl    Propyl                   1077           NO    4             Methyl    Ethyl    Butyl                    1078           NO    4             Methyl    Propyl   Propyl                   1079           NO    4             Methyl    Propyl   Butyl                    1080           NO    4             Methyl    Butyl    Butyl                    1081           NO    2             Butyl     H        H                        1082           NO    2             Butyl     H        Methyl                   1083           NO    2             Butyl     H        Ethyl                    1084           NO    2             Butyl     H        Propyl                   1085           NO    2             Butyl     H        Butyl                    1086           NO    2             Butyl     Methyl   Methyl                   1087           NO    2             Butyl     Methyl   Ethyl                    1088           NO    2             Butyl     Methyl   Propyl                   1089           NO    2             Butyl     Methyl   Butyl                    1090           NO    2             Butyl     Ethyl    Ethyl                    1091           NO    2             Butyl     Ethyl    Propyl                   1092           NO    2             Butyl     Ethyl    Butyl                    1093           NO    2             Butyl     Propyl   Propyl                   1094           NO    2             Butyl     Propyl   Butyl                    1095           NO    2             Butyl     Butyl    Butyl                    1096           NO    1             Ethyl     H        H                        1097           NO    1             Ethyl     H        Methyl                   1098           NO    1             Ethyl     H        Ethyl                    1099           NO    1             Ethyl     H        Propyl                   1100           NO    1             Ethyl     H        Butyl                    1101           NO    1             Ethyl     Methyl   Methyl                   1102           NO    1             Ethyl     Methyl   Ethyl                    1103           NO    1             Ethyl     Methyl   Propyl                   1104           NO    1             Ethyl     Methyl   Butyl                    1105           NO    1             Ethyl     Ethyl    Ethyl                    1106           NO    1             Ethyl     Ethyl    Propyl                   1107           NO    1             Ethyl     Ethyl    Butyl                    1108           NO    1             Ethyl     Propyl   Propyl                   1109           NO    1             Ethyl     Propyl   Butyl                    1110           NO    1             Ethyl     Butyl    Butyl                    1111           NO    3             Ethyl     H        H                        1112           NO    3             Propyl    H        Methyl                   1113           NO    3             Propyl    H        Ethyl                    1114           NO    3             Propyl    H        Propyl                   1115           NO    3             Propyl    H        Butyl                    1116           NO    3             Propyl    Methyl   Methyl                   1117           NO    3             Propyl    Methyl   Ethyl                    1118           NO    3             Propyl    Methyl   Propyl                   1119           NO    3             Propyl    Methyl   Butyl                    1120           NO    3             Propyl    Ethyl    Ethyl                    1121           NO    3             Propyl    Ethyl    Propyl                   1122           NO    3             Propyl    Ethyl    Butyl                    1123           NO    3             Propyl    Propyl   Propyl                   1124           NO    3             Propyl    Propyl   Butyl                    1125           NO    3             Propyl    Butyl    Butyl                    __________________________________________________________________________ 

We claim:
 1. A compound of the formula ##STR645## wherein X is ##STR646## 55 or ═N--O--, in which R₄ is hydrogen or halogen, R₁, R₂, and R₃ independently represent hydrogen or a C₁₋₄ alkyl group, and n is an integer having a value of zero to four inclusive and pharmaceutically acceptable salts thereof.
 2. The compound of claim 1 wherein R₁, R₂ and R₃ independently represent hydrogen or a methyl group and pharmaceutically acceptable salts thereof.
 3. The compound of claim 1 wherein n has a value of zero to two and pharmaceutically acceptable salts thereof.
 4. The compound of claim 1 wherein X is ##STR647## in which R₄ is hydrogen or halogen and pharmaceutically acceptable salts thereof.
 5. The compound of claim 1 wherein X is ═H--O-- and pharmaceutically acceptable salts thereof.
 6. A pharmaceutical composition comprising an effective amount of the compound or salt of claim 1 admixed with a pharmaceutically acceptable carrier.
 7. A method to block N-methyl-D-aspartate receptors comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim
 6. 8. A method to treat pathosis or diseases having a relation with N-methyl-D-aspartate receptors comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim
 6. 9. A method to treat cerebral ischemia, cerebral hypoglycemia, epilepsy, anxiety or convulsion comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim
 6. 